Muscle-invasive Urothelial Carcinoma Of Bladder Research Articles

2024TiP NETOS: A personalized approach of neoadjuvant therapy, including INCB099280 monotherapy and bladder preservation, for muscle-invasive urothelial bladder carcinoma (MIBC) with ctDNA monitoring

2024TiP NETOS: A personalized approach of neoadjuvant therapy, including INCB099280 monotherapy and bladder preservation, for muscle-invasive urothelial bladder carcinoma (MIBC) with ctDNA monitoring

Muscle-invasive and metastatic urothelial carcinoma of the urinary bladder : Current state of histopathologic, molecular, and immunologic prognostic and predictive factors

Muscle-invasive and metastatic urothelial carcinoma (UC) represents aheterogeneous disease entity with numerous morphological, molecular, and immunological phenotypes. This article aims to provide an overview of current histopathological, molecular, and immunological prognostic and predictive factors in muscle-invasive and metastatic UC. Muscle-invasive and metastatic UC exhibits awide range of divergent differentiations and histological subtypes. The correct diagnosis of these morphological variants is essential, as they may determine the clinical course and may also present specific and potentially therapeutically targetable molecular alterations (e.g., HER2 alterations in micropapillary UC). The morphological subtypes largely correlate with the six molecular consensus subtypes. Furthermore, morphological and molecular subtypes are associated with immunological properties that are relevant for modern immunotherapies, such as the PD-L1 status. Numerous immunotherapy studies in the setting of curatively treatable muscle-invasive UC will be reported in 2024 and 2025, likely leading to an increasing number of PD-L1 testing indications.

NETOS: A personalized approach of neoadjuvant therapy, including INCB099280 monotherapy and bladder preservation, for muscle-invasive urothelial bladder carcinoma (MIBC) with ctDNA monitoring.

TPS4624 Background: MIBC is a systemic disease as >40% of patients (pts) ultimately develop recurrence after radical cystectomy (RC). For pts who cannot receive or refuse cisplatin-based chemotherapy there is no standard-of-care neoadjuvant therapy. Single-agent pembrolizumab, given neoadjuvantly in patients with T2-4N0M0 MIBC, was effective in PURE-01 trial. A proportion of these pts refused RC and were cured with pembro and redo transurethral resection of the bladder tumor (reTURBT; Bandini et al. PMID: 32979511). There are increasing concerns by the pts related to the need to undergo RC whenever they achieve a clinical complete response (cCR) with TURBT and systemic therapy. INCB099280 is a potent, orally bioavailable, selective, small molecule that targets PD-L1 that is being developed for the treatment of advanced malignant diseases. A phase 1, dose-escalation and expansion study is ongoing in pts with select advanced solid tumors (NCT04242199); safety and preliminary efficacy results have been reported (Prenen et al. ESMO-IO 2023). Our hypothesis is that INCB099280 can be offered in biomarker-selected pts as a maintenance therapy instead of any additional treatment, provided that a cCR after the induction phase is obtained. Methods: Pts should have a predominant urothelial carcinoma (UC) histology, have a clinical stage T2-T4N0M0 MIBC, be ineligible for or refuse to receive cisplatin-based chemotherapy. The study will also select pts with a circulating tumor DNA (ctDNA)-positive test (Signatera ctDNA assay) and will be staged with pelvic MRI. Pts will receive 12 weeks of INCB099280 at the dose of 400 mg twice daily (BID), continuously. Restaging will be planned with ctDNA, imaging and reTURBT. Pts who will achieve a cCR (i.e., no evidence of residual disease at the histological examination, clearance of ctDNA and the evidence of no residual detectable disease at cross-sectional imaging, evaluated locally) will receive additional INCB099280 400 mg BID for a maintenance period of 12 months. Pts with evidence of high grade or infiltrating residual disease will be discontinued from the study. Those with a Ta/T1-low grade disease will be managed according to physician’s preference: they may be eligible to continue within the study protocol and receive maintenance INCB099280 400 mg BID for a total period of 12 months. The primary endpoint is the proportion of cCR and the study is planned according to A'Hern one-stage binomial design, with H0 ≤5% and H1 ≥20%, 5% one-sided Alpha, 80% power and 10% drop-out rate. The overall sample size Will be of 30 pts. Secondary endpoints will include safety (CTCAE v.5.0), event-free survival, bladder-intact overall survival (OS) and OS (EUCT number: 2024-511029-73-00). Clinical trial information: 2024-511029-73-00.

Temporal Trends and Cancer-Specific Mortality in Nonmetastatic Muscle-Invasive Urothelial Carcinoma of the Urinary Bladder Treated With Trimodal Therapy

IntroductionTrimodal therapy (TMT) is guideline-recommended for the management of organ confined urothelial carcinoma of urinary bladder (UCUB). However, temporal trends in TMT use and cancer-specific mortality free-survival (CSM-FS) between historical TMT versus contemporary TMT have not been assessed. We addressed this knowledge gap. Material and MethodsWithin the Surveillance, Epidemiology, and End Results database (2004–2020), we identified nonmetastatic UCUB patients with cT2-T4aN0-N2 treated with TMT, defined as the combination of transurethral resection of bladder tumor, chemotherapy and radiotherapy. Temporal trends described TMT use over time. Subsequently, patients were divided between historical (2004-2012) versus contemporary (2013-2020) cohorts. Survival analyses consisting of Kaplan–Meier plots and multivariable Cox regression (MCR) models addressed CSM-FS. Separate analyses addressed patients with organ confined (OC: cT2N0M0) versus nonorgan confined (NOC: cT3-4a and/or cN1-2) clinical stages. ResultsOf 4,097 assessable UCUB TMT patients, 1744 (43%) were treated in the historical period (2004-2012) versus 2353 (58%) in the contemporary period (2013-2020). TMT use increased over time in OC patients (EAPC:+3.4%, P < .001), as well as in NOC (EAPC:+2.7%, P < .001). In OC stage, median CSM-FS was 55.3% in historical versus 49.0% in contemporary patients (HR:0.75, P < .001). Similarly, in NOC stage, 5-year median CSM-FS was 43.0% in historical versus 32.8% in contemporary patients (HR:0.78, P = .01). ConclusionTMT rates have increased over time in both OC and NOC patients. Contemporary TMT patients benefit of better cancer-specific survival. Interestingly, this benefit applies equally to OC and NOC TMT-treated patients.

How Immunotherapy Has Redefined the Treatment Paradigm of Metastatic or Locally Advanced Muscle-Invasive Urothelial Bladder Carcinoma.

In the past decade, the therapeutic arsenal for metastatic bladder cancer has expanded considerably, with the development of immune checkpoint inhibitors (ICIs), antibody-drug conjugates such as enfortumab vedotin, and anti-fibroblast growth factor receptor agents. Clinical trials evaluating ICIs as neoadjuvants, adjuvants, or first- or second-line treatments have produced conflicting results. However, first-line therapeutic strategies have been redefined by the recent publication of results from two clinical trials: CheckMate-901, which demonstrated the superiority of combined treatment with nivolumab and chemotherapy in extending overall survival, and EV-302, which demonstrated that combined treatment with pembrolizumab and enfortumab vedotin reduced the risk of death by 53%. In this review, we discuss the role of ICIs, alone or in combination, in bladder cancer management in the metastatic and adjuvant settings in 2024, considering the latest published trials. The potential role of ICIs as neoadjuvants is also discussed.

The role of androgen response pathway in association with tumor biology and response to neoadjuvant immune-checkpoint inhibitors (ICI) in muscle-invasive urothelial bladder carcinoma (MIBC).

662 Background: Emerging findings from ICI trials are suggestive of differential outcomes in females compared with males. Sex-specific differences in tumor biology, microbiome, and outcomes in MIBC are well-established. Conversely, limited data are available regarding the role of the androgen response pathway in explaining subtype differences between males and females and, most importantly, response to ICI. Methods: We retrospectively evaluated the biomarker findings of the transurethral resection of the bladder tumors (TURBT) and baseline clinical characteristics of patients (pts) with cT2-4N0M0 MIBC who received neoadjuvant pembrolizumab and radical cystectomy (RC) in the PURE-01 study. Transcriptome-wide expression profiling was performed on 102 TURBT samples. We focused on androgen receptor (AR) gene expression and the hallmark androgen response pathway expression quantifying 117 different genes related to the androgen response pathway as previously reported (PMID: 26771021). Pt and tumor characteristics were compared between subgroups using χ2 tests and two-sided Wilcoxon rank-sum tests. Kaplan-Meier curves and log rank tests evaluated gene expression and signature scores in association with the event-free survival (EFS), calculated from start of pembrolizumab treatment. Signature scores were analyzed as continuous values and were split by median and quartile values. Results: Pts received pembrolizumab and RC from 2017 to 2022. There were 87 (85.3%) males and 15 (14.7%) females. AR gene expression was not significantly different between males and females (p = 0.5), whereas androgen response signature was significantly higher in male (p = 0.03). The AR gene expression and androgen response signature scores were more highly expressed in luminal tumors vs rest of molecular subtypes (p = 0.005 and p &lt; 0.001). Despite AR gene expression was not associated with ypT0N0 response (p = 0.425), hallmark androgen response signature scores were significantly lower in ypT0N0 responders (p = 0.033). Higher hallmark androgen response signature scores were statistically significantly associated with shorter EFS (p = 0.028), whereas AR gene expression was not (p = 0.152). Conclusions: For the first time to our knowledge, we reported the androgen response pathway expression to be a potential biomarker of ICI benefit in MIBC. This signature was also associated with a luminal subtype, linked to inferior responsiveness to ICI. If confirmed at a larger scale these analyses will strengthen the need for sex-specific approaches and potentially new combination therapies in MIBC.

Comparative Effectiveness of Neoadjuvant Pembrolizumab Versus Cisplatin-based Chemotherapy or Upfront Radical Cystectomy in Patients with Muscle-invasive Urothelial Bladder Cancer

BackgroundRecent progresses in the use of immune checkpoint inhibitor (ICI) have challenged the therapeutic standards in patients with muscle-invasive urothelial bladder carcinoma (MIBC). ObjectiveTo compare neoadjuvant pembrolizumab followed by radical cystectomy (RC) versus neoadjuvant chemotherapy (NAC) and RC or upfront RC, according to cisplatin eligibility. Design, setting, and participantsWe conducted two separate analyses for cisplatin-eligible and cisplatin-ineligible cT2-4N0M0 MIBC patients. We used a propensity score adjustment that relied on inverse probability of treatment-weighting (IPTW). InterventionPembrolizumab within the PURE-01 trial, and NAC and RC or upfront RC from a high-volume tertiary care referral center. Outcome measurements and statistical analysisThe primary endpoint in both analyses was event-free survival (EFS), defined as freedom from recurrence, and/or death from any cause indexed from the date of treatment initiation or RC. The secondary endpoints included EFS in propensity score–matched patients, pathologic response rate, and recurrence-free survival (RFS) after RC. Results and limitationsA total of 458 patients who underwent RC, with or without NAC, at Moffitt Cancer Center between October 2005 and October 2020, and 146 patients enrolled in PURE-01 were analyzed. In cisplatin-ineligible patients, EFS was superior in those receiving pembrolizumab (p < 0.001). The estimated 3-yr EFS was 77.8% (95% confidence interval [CI]: 63.5–95.2) for pembrolizumab and RC, and 36.1% (95% CI: 28.6–45.5) for upfront RC. EFS remained superior in those receiving neoadjuvant ICI (NICI) following IPTW (p < 0.001). In cisplatin-eligible patients, EFS was superior in those receiving pembrolizumab and RC (p < 0.001). The estimated 3-yr EFS was 86.9% (95% CI: 80.9–93.3) for pembrolizumab and 63.5% (95% CI: 56.5–71.4) for NAC. EFS remained superior in those receiving NICI following IPTW (p < 0.001). Pathologic responses and RFS in pembrolizumab-treated patients were also superior to those in NAC-treated patients. Results are limited by the retrospective nature of the study. ConclusionsIn the first ever reported comprehensive comparison of outcomes between neoadjuvant ICI and NAC, followed by RC, or upfront RC, we report increased responses and improved oncologic outcomes with neoadjuvant ICI in patients with MIBC. Patient summaryWe compared the results obtained from the use of pembrolizumab and radical cystectomy with standard-of-care treatments in patients with bladder carcinoma infiltrating the muscle layer. We reported increased response and survival rates possibilities with the use of immunotherapy, anticipating the possibility to set new therapeutic standards in these patients, pending the results of ongoing randomized studies.

Prognostic Significance of Lymph Node Density in Pathological Node Positive Urothelial Carcinoma of the Bladder -Upfront Surgery and Post Neoadjuvant Chemotherapy Cohorts

AimTo validate the role of lymph node density as a prognostic marker in patients undergoing primary surgery and postneoadjuvant therapy in pathological node-positive urothelial bladder carcinoma. Materials and MethodsRetrospective analysis of 503 patients who underwent radical cystectomy from 2006 to 2019 for muscle-invasive urothelial bladder carcinoma, of which 152 patients with pathological node-positive disease were analyzed. Demographic details, pathological findings, treatment details, disease-free, and overall survival were documented. X tile program analysis was used to divide patients with positive lymph nodes into 3 groups: LD1: <= 7, LD2 :>7 to <15, LD3: >15, and the optimal cut-off value obtained was 15%. To evaluate the impact of lymph node ratio, patients with positive lymph nodes into 3 categories for each cut-off point estimation method, the application generates the histogram, Kaplan–Meier plot and calculates hazard ratio, confidence intervals and P-values. Univariate and multivariate cox regression analysis was done with a P-value of <.05, considered significant. ResultsOne hundred fifty-two patients (30.2%) had pathological nodal metastasis, with 87 of them having perinodal extension. Ninety-six underwent primary surgery, and 56 were postneoadjuvant chemotherapy. The median follow-up was 55.42 months. 68 of the 152 node-positive patients died of the disease. Median number of lymph nodes removed was 17.11. Lymph node density divided into tertiles were LD1 <7%, LD2 7-<15%, LD3 >15% showed 5-year RFS 40.5%,29.3%, 22.6% and 5 year OS was 55.5%, 42.4%,32.1% respectively. Cox regression analysis showed that age less than 55 years ,higher tumor stage, lymphovascular invasion, and higher lymph node ratio were significant in univariate and multivariate analysis. The lymph node density cut-off value of 15% was substantial among node-positive patients (P = .027), and subgroup analysis in upfront surgery with the adjuvant treatment group and postneoadjuvant chemotherapy group was also significant (P =.021). ConclusionPathological higher T stage, Age <55 years, Lymphovascular invasion, adjuvant chemotherapy , adjuvant radiation treatment and lymph node density had prognostic significance in both cohorts of patients who underwent upfront surgery and neoadjuvant chemotherapy. Lymph node density cut-off value of <15% was prognostically significant.

Fibroblast growth factor receptor 3 (FGFR3) alterations in PROOF 302: A phase III trial of infigratinib (BGJ398) as adjuvant therapy in patients (pts) with invasive urothelial carcinoma (UC).

4511 Background: Radical surgery with or without (neo)adjuvant cisplatin-based chemotherapy [(N)AC] is standard in fit pts with muscle invasive UC of bladder (UBC) or upper tract (UTUC). However, recurrence rates are high, underscoring the need for novel therapies. Since up to 70% of UTUC and 20% of UBC tumors were reported to harbor FGFR3 alterations, targeting this pathway is a rational approach. Infigratinib is a selective FGFR1–3 inhibitor with efficacy in advanced UC with FGFR3 alterations [Pal et al. 2018]. PROOF 302 investigated the efficacy and safety of adjuvant infigratinib vs placebo in pts with high-risk invasive UC. Methods: PROOF 302 was a global, randomized, double-blind, placebo-controlled, phase III trial for pts with high-risk invasive UTUC or UBC (≤15%) with FGFR3 alteration (i.e. mutation, gene fusion / translocation) with residual (≥ypT2 and/or ypN+) tumor after NAC, or pts ineligible for, or refusing, cisplatin-based AC, ≤120 days post-surgery. Pts were randomized 1:1 to infigratinib 125 mg or placebo daily on days 1–21 every 28 days for up to 52 weeks or until recurrence, unacceptable toxicity, or death. Primary endpoint: centrally reviewed disease-free survival (DFS). Secondary endpoints: investigator-assessed DFS, metastasis-free survival, overall survival, safety/tolerability. Exploratory endpoints: QOL, pharmacokinetics, genomic analysis of tumor and cfDNA. Assessment of genomic alterations was pursued using descriptive statistics. Results: We present the results of the genomic analysis of radical surgery tissues from pts screened for the trial using the FoundationOne platform. Out of 617 pts screened, 188 (30.5%) had alterations in FGFR 1-4 genes: 102/237 (43%) in UTUC, 85/369 (23%) in MIBC and 1/11 (9%) with unknown tumor origin. Of these 188 pts, median age 74 (32-90 years), 76% were male, 55% had UTUC, 44% had UBC. Genomic alterations are shown. In UTUC, FGFR3 had 56% single-nucleotide variations (SNV) and insertions/deletions (INDELS), 40% amplifications and 70% structural variants (SV). In UBC, FGFR3 had 44% SNV and INDELS, 60% amplifications and 30% SV. Conclusions: FGFR3 alterations were seen in only 19% of all pts screened for PROOF-302, a trial that was enriched for UTUC: 71/237 (30%) of UTUC and 48/369 (13%) of UBC. The trial was stopped early by the sponsor, but the genomic analysis provides insights into the prevalence of FGFR3 alterations; assessment of correlations with the primary/secondary endpoints is ongoing. The nature and frequency of co-occurring alterations in tissue samples is being investigated to help inform combination therapy strategies and putative resistance mechanisms. Clinical trial information: NCT04197986 . [Table: see text]

Abstract 6658: Prevalence of PD-L1 expression and its correlation with tumor biomarkers in the Chinese muscle invasive urothelial bladder carcinoma patients

Abstract The association of programmed cell death-ligand 1 (PD-L1) expression with the activity of immune checkpoint inhibitor therapy setting has encouraged us to study the prevalence of PD-L1 in muscle invasive urothelial bladder cancer (MIUBC) patients. Since, the prevalence of PD-L1 expression and its prognostic role in MIUBC is unclear in China, we conducted a multi-center, prospective, epidemiological study to investigate prevalence of high PD-L1 expression and its correlation with other exploratory biomarkers including CD8+ T cells and tumor mutation burden (TMB) in Chinese MIUBC patients (NCT03433924). The study enrolled newly diagnosed, untreated MIUBC patients from 17 hospitals in China. High PD-L1 expression by Ventana PD-L1 [SP263] assay was defined as 1) ≥25% tumor cell (TC) + or 2) tumor associated immune cell (IC) area &amp;gt;1%: ≥25% IC+; 3) IC area=1%: 100% IC+. The primary outcome was prevalence of high PD-L1 expression; secondary outcome was PD-L1 expression profile in TC or IC in patients. An exploratory study was conducted to investigate the percentage of patients with high infiltration of CD8+ T cells and elevated TMB using immunohistochemistry and next generation sequencing, respectively. High CD8+ and TMB status was considered if it refers to ˃ median value (3%) and ˃10 mut/Mb, respectively. Association of PD-L1 expression with demographic and baseline characteristics was evaluated by logistic regression model while PD-L1 with tumor biomarkers were evaluated by spearman’s rank correlation coefficient. Overall, 248 MIUBC patients were enrolled and 229 patients with PD-L1 data were included. High PD-L1 expression was observed in 52.4% patients. High PD-L1 expression was positive in 59 (25.8%) patients of TC and 82 (35.8%) patients of IC. CD8+ T cell and TMB showed high expression in 44.5% and 54.1% patients, respectively, with mean TMB of 14.14 mut/Mb. The exploratory analysis showed no significant association of PD-L1 expression with age, gender, primary tumor site, metastatic disease, regional lymph node, tobacco use or AJCC stage. Further a weak and positive correlation was observed between percentage of TC with membrane PD-L1 positivity and CD8+ T cells (0.34, 95%Cl, 0.22 - 0.45, p˂0.001), IC with membrane PD-L1 positivity and CD8+ T cells (0.44, 95%Cl, 0.33 - 0.54, p˂0.001), TC with membrane PD-L1 positivity and TMB (0.05, 95%Cl, -0.08 - 0.19, p=0.441), IC with membrane PD-L1 positivity and TMB (0.16, 95%Cl, 0.02 - 0.29, p=0.020). In conclusion, our study showed high prevalence of PD-L1 expression in patients with MIUBC along with their weak, positive correlation with CD8+ T cells and TMB. These findings are consistent with other studies that show that PD-L1 and TMB stand as the most robust predictive biomarkers, but may be uncorrelated. With subsequent follow-up time, the effect of biomarkers on survival will be assessed in future study. Citation Format: Yu Fan, Tao Dai, Dahong Zhang, Hongqian Guo, Fangjian Zhou, Benkang Shi, Shaogang Wang, Zhigang Ji, Chunxi Wang, Xudong Yao, Qiang Wei, Nanhui Chen, Jinchun Xing, Jinjian Yang, Chuize Kong, Jian Huang, Dingwei Ye, Liqun Zhou. Prevalence of PD-L1 expression and its correlation with tumor biomarkers in the Chinese muscle invasive urothelial bladder carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6658.

A prospective phase II trial of neoadjuvant sintilimab in muscle-invasive urothelial carcinoma of bladder.

509 Background: To assess the efficacy and safety of the PD-1 antibody in neoadjuvant setting of muscle-invasive urothelial carcinoma of bladder (MIBC). Methods: In this prospective phase II trial (ChiCTR2000032730), eligible patients were cT2-T4 N0 MIBC, and were considered eligible for radical cystectomy (RC). Patients received sintilimab 200 mg on days 1, study treatment was repeated every 21 days up to 3 cycles before surgery. The primary endpoint was pathologic complete response (pCR, ypT0). Secondary endpoints included incidence of surgical related delayed events, relapse free survival, overall survival and safety. Results: Between Aug 2020 and Sep 2022, 15 patients (median age: 69, male 93.3%, PS=1 100%) were enrolled. The majority of patients (93.3%) completed the planned (median, 3; range 2 to 4) cycles of sintilimab without significant toxicities. The most common adverse events included hematuria (3/15), proteinuria (2/15), hypophosphatemia (2/15), hypoalbuminemia (2/15) and dysuria (2/15). Among the 15 patients who completed study treatment, 9 patients (60.0%) received RC. Among 6 patients who did not revive RC, 1 due to myasthenia gravis related to sintilimab, 1 due to progression disease, 3 patients refused RC due to bladder preserving, and 1 due to cardiac comorbidity unrelated to sintilimab. Pathologic results revealed 6 pCR (ypT0, 66.7%), 1 ypT0N1, 1 ypT2N0 and 1ypT4N0. At a median follow up of 181 days, they all had no disease recurrence and median DFS was not reached. 2 patients died of disease progression (1 refused RC, 1 had PD before RC). Conclusions: Neoadjuvant sintilimab was feasible and provided meaningful pathologic responses in patients with MIBC. Clinical trial information: ChiCTR2000032730 .

Neoadjuvant cisplatin-based chemotherapy followed by selective bladder preservation chemoradiotherapy (CRT) in muscle-invasive urothelial carcinoma of bladder (MIBC): A combined retrospective analysis of two prospective studies.

496 Background: Bladder preservation CRT in patients with a clinical complete response (cCR) following neoadjuvant cisplatin-based chemotherapy is one of the promising treatment strategies for MIBC. A combined analysis of raw data from two prospective phase II studies was performed to better evaluate the feasibility of selective bladder preservation CRT. Methods: The analysis was based on primary efficacy data from two independent studies, including 76 MIBC patients receiving neoadjuvant chemotherapy followed by bladder preservation CRT. The efficacy data included metastasis-free survival (MFS) and disease-free survival (DFS). For the present analysis, starting point of survivals was defined as the date of commencing CRT. Results: Sixty-four patients received gemcitabine/cisplatin (GC) combination chemotherapy in neoadjuvant setting, and 12 received nivolumab plus GC. After completion of planned neoadjuvant chemotherapy, 66 patients with a cCR and 10 who did not have a cCR but refused surgery were treated with CRT. With a median follow-up of 45 (95% CI, 41-48) months, a total of 39 recurrences was observed (51%): metastatic (n=28) and within the urinary tract (n=11). Median DFS or MFS was not reached. The 12- and 24-month DFS rates were 81% and 66%, respectively. MFS rates at 12- and 24-month were 87% and 75%, respectively. Both DFS (P=0.055) and MFS (P=0.014; HR 0.38; 95% CI, 0.17-0.85) appeared to be affected by the achievement of a cCR. Conclusions: The strategy of neoadjuvant chemotherapy followed by selective bladder preservation CRT based on the cCR is feasible in the treatment of MIBC.

152P An epidemiologic study on PD-L1 expression with clinical observation of initial treatment pattern in the Chinese muscle invasive urothelial bladder carcinoma patients

There is no relevant data of real-time programmed cell death-ligand 1 (PD-L1) expression and initial treatment pattern in Chinese muscle invasive urothelial bladder carcinoma patients (MIUBC). Thus, the aim of this multi-center, prospective, epidemiological study was to investigate the prevalence of high PD-L1 expression along with clinical observation of initial treatment pattern in the Chinese MIUBC patients (NCT03433924).

Phase II clinical study of tislelizumab combined with nab-paclitaxel (TRUCE-01) for muscle-invasive urothelial bladder carcinoma: Bladder preservation subgroup analysis.

4589 Background: The current strategy for bladder preservation is focused on trimodality treatment, including complete transurethral resection of bladder tumor (cTURBT), with concurrent chemotherapy and radiotherapy. Chemotherapy is usually a cisplatin-based regimen. However, many pts cannot tolerate cisplatin-based chemotherapy and radiation therapy. It fails to meet clinical needs. Meanwhile, the efficacy and safety of checkpoint inhibitors (ICIs) have now been demonstrated. We conduct a study to evaluate ICIs in combination with second-line chemotherapy agents for patients with MIBC. Methods: TRUCE-01 is a phase II trial (NCT04730219) of tislelizumab combined with nab-paclitaxel before cTURBT or radical cystectomy. Pts with pure or mixed urothelial bladder cancer (T2-4a Nx M0) received tislelizumab 200mg on days 1 plus paclitaxel 200mg on days 2 every 3 weeks (Q3W) x 3 cycles followed by cTURBT or radical cystectomy. Imaging evaluation is usually done before and after the drug administration using the same tests to assess the efficacy. Pts who choose to preserve bladder usually continue their medication after cTURBT. This abstract focuses on patients with bladder preservation. Results: Between July 2020 and November 2021, 47 pts completed at least 2 cycles of treatment, 22 (47%) pts received cTURBT, 16 (34%) pts received radical cystectomy and 9 (19%) pts refuse surgery. As for radiological response, 22 achieved complete response (CR), 16 achieved partial response (PR). In the bladder-preserving subgroup, 13 CR pts and 9 PR pts selected cTURBT, pathology showed 17 pT0, 1 pTa, 3 pT1 and 1 pTis. The median medication cycle is 9 (6-11). There were 3 pts experienced grade 3-4 adverse events (CTCAE), a grade 3 rash, a grade 3 gastric perforation and a grade 4 acute renal failure. In addition, The most common grade 1-2 adverse events include alopecia (86%), fatigue (77%), rash (41%), appetite decreases (41%), hyperglycemia (36%), fever (18%), and creatinine increased (14%). Median follow-up 357 (438-291) days with 3 recurrences and 1 death. The 1-year recurrence-free survival rate was 82%. Conclusions: The early efficacy data further support the role of tislelizumab combined with paclitaxel in bladder preservation setting with an acceptable adverse events. Patients with imaging CR or PR after neoadjuvant therapy are preferred for bladder preservation. Enrollment is ongoing. Clinical trial information: NCT04730219.

An open-label, phase 2 study of personalized approach with perioperative immunotherapy for bladder preservation in muscle-invasive urothelial bladder carcinoma (MIBC).

TPS590 Background: Radical cystectomy (RC) without neoadjuvant chemotherapy is standard-of-care for cisplatin (cis)-ineligible pts (and those refusing cisplatin) with MIBC. Checkpoint inhibitors (CPIs) are being actively explored in the perioperative setting. CPIs documented a 42% pathologic complete response-rate (ypT0N0) in our previous trial (PURE-01, NCT02736266). In this trial, programmed cell-death ligand-1 (PD-L1) expression was associated with ypT0N0 response ( Necchi A, et al. Eur Urol. 2019), and a cohort of PD-L1+ pts who refused RC are still alive at long-term follow-up ( Bandini, Ann Oncol 2020). Initial data from trials aimed at delivering a systemic therapy while sparing any local therapy on the bladder tumor in highly-selected pts are promising ( Galsky, 2021, Geynisman, 2021). Sasanlimab (SASI) is a humanized, hinge region–stabilized (21) IgG4 mAb directed against human PD-1. Sasanlimab is currently being tested subcutaneously (SQ) in a phase III study in non-MIBC. Our hypothesis is that SASI can be offered in PD-L1+ pts as an exclusive therapeutic option instead of any additional treatment, after a clinical complete response (cCR) with an induction phase. Methods: This is a Phase 2, open-label, non-randomized, single-cohort study in pts with MIBC who are ineligible or unwilling to receive cisplatin-based neoadjuvant chemotherapy. The study will include pts with a PD-L1 CPS≥10% in tumor biopsy.Other key inclusion criteria: UC histology, an ECOG PS 0−1. Cis-ineligibility is defined as one of the following: glomerular filtration rate ≥30 but &lt; 60 mL/min, or CTCAE v5 ≥grade 2 hearing loss or peripheral neuropathy. Key exclusion criteria: clinical evidence of ≥N1 or metastatic disease or UC in upper urinary tract; prior systemic therapy, radiation therapy, or prior RC. Pts will undergo a transurethral resection of the bladder (TURBT), a CT scan, and a 18FDG-PET/CT scan. SASI will be administered SQ at the recommended dose of 300mg for a total of 3 cycles every 4 weeks prior to redo-TURBT. Pts who will achieve a cCR (i.e., no evidence of residual viable tumor at re-TURBT sample, urinary cytology and imaging tests) will receive additional SASI treatment for a total period of 12 months, every 4 weeks. Pts with non-CR will be excluded from the study and start treatment according to guidelines or investigator preference. Primary endpoint: event-free survival (EFS). Secondary endpoint: proportion of cCR. According to Simon's 2-stage MinMax design, a total of 55 pts will be included, and we anticipate the need for enrolling 110 pts for the neoadjuvant phase of the study. This assumption will correspond to the need for screening approximatively 220 pts onto this trial. Exploratory analyses will include: artificial intelligence through multiparametric bladder MRI/PET, and ctDNA analyses pre-post neoadjuvant period. Clinical trial information: 2021-001649-10.

A prospective phase II trial of neoadjuvant nivolumab plus gemcitabine/cisplatin chemotherapy in muscle-invasive urothelial carcinoma of bladder.

494 Background: To assess the efficacy and safety of the combination of nivolumab plus gemcitabine/cisplatin in neoadjuvant setting of muscle-invasive urothelial carcinoma of bladder (MIBC). Methods: In this prospective phase II trial (CRIS, KCT0003804), eligible patients had cT2-T4a N0 MIBC, cisplatin-eligible, and to be planned radical cystectomy. Patients received nivolumab 3 mg/kg on days 1 and 15, cisplatin 70 mg/m2 on day 1, and gemcitabine 1,000 mg/m2 on days 1, 8 and 15. Study treatment was repeated every 28 days up to 3 or 4 cycles, depending on the surgery schedules. The primary endpoint was pathologic complete response (pCR, ypT0). Secondary endpoints included pathologic downstaging (&lt;ypT1), disease-free survival (DFS) and safety. Results: Between Sep 2019 and Oct 2020, 51 patients were enrolled. The majority of patients (96%) completed the planned (median, 3; range 1 to 4) cycles of nivolumab plus gemcitabine/cisplatin without significant toxicities. The most commonly observed adverse events included fatigue, nausea and pruritus. Among the 49 patients who completed study treatment, 12 patients refused surgery but were treated with concurrent chemoradiotherapy. Radical cystectomy was performed in 34 (69%) patients. Pathologic results revealed 12 pCR (ypT0, 35%), 4 ypTis, 3 ypTa, 3 ypT1, and 12 ypT2/T3. Preoperative PD-L1 (22C3 TPS&gt;1%) did not correlate with pCR or pathologic downstaging rates. With a median follow-up of 19 months (95% CI, 17 to 20), 12 patients experienced disease recurrence and median DFS was not reached. Conclusions: Neoadjuvant nivolumab plus gemcitabine/cisplatin was feasible and provided meaningful pathologic responses in patients with MIBC. Clinical trial information: KCT0003804.

Dysfunctional Voiding- Presentation of a Rare Case of Pediatric Non Muscle Invasive Urothelial Bladder Carcinoma

Bladder cancer is rare in children, with 86.8% of pediatric patients diagnosed not carrying any of the common risk factors commonly seen in adults. Here, a 16-year-old female presented to the ED with in urinary retention. A renal bladder ultrasound revealed an echogenic focus in the bladder wall. On diagnostic cystoscopy a small papillary bladder lesion was appreciated and resected. Final pathology of the bladder mass resulted as non-invasive low grade papillary urothelial carcinoma (pTa). This report demonstrates bladder cancer in the pediatric age group, and should be considered as a possible differential diagnosis in patients with dysfunctional voiding.

Effect of HER2 and Fascin expression on muscle-invasive bladder cancers: Classification by basaloid and luminal phenotypes

The present study aims to identify basaloid and luminal molecular groups and the p53-like sub-group, which is a sub-group of the luminal group, using a specific immunohistochemical panel and investigate human epithelial growth factor receptor 2 (HER2)/Neu and Fascin expression in these groups to analyze their relationship with clinicopathological features and prognosis in a cohort of cases with muscle-invasive urothelial bladder carcinoma (MIBC). An immunohistochemical panel that included GATA-3, CK20, CD44, and CK5/6 was used to identify molecular sub-groups based on expression in 44 cases of MIBC. HER2/Neu and Fascin expression in basal, luminal, and p53-like groups and the relationship with clinicopathological features and prognosis were investigated. The distribution of the molecular sub-groups determined by immunohistochemistry was as follows: 23 luminal cases (52.3%), 16 basal cases (36.4%), and 5 (11.4%) p53-like cases. There was a statistically significant difference in tumor size across the groups, with the greatest size in the p53-like group (p = 0.001). A statistically significant difference was observed in HER2/Neu expression between the molecular sub-groups (p = 0.017). Comparison of survival and HER2/Neu scores revealed shorter survival in patients with an HER2/Neu score of 3 + compared to those with scores of 0, 1+, and 2+ (p = 0.109). Fascin immunoreactivity was more common in the p53-like and basal groups compared to the luminal group (p = 0.036). Despite the limited number of cases in the MIBC group, our results support that HER2/Neu expression in the luminal sub-group and Fascin expression in basal and p53-like groups may be used as a negative prognostic marker. Multi-center studies that include large case series are warranted in this field.

The Bladder Microbiome Is Associated with Epithelial-Mesenchymal Transition in Muscle Invasive Urothelial Bladder Carcinoma.

Simple SummaryThe abundance of microbial species residing within tumors is correlated to cancer progression across many different cancers, including bladder cancer. However, links between the intratumor microbiome of muscle invasive bladder cancer (MIBC) and specific mechanisms of cancer progression have not been well studied. In this paper, we aim to uncover the relationship between microbial abundance in the MIBC intratumor microbiome and epithelial–mesenchymal transition (EMT), one key feature of cancer progression. By comparing the gene expression of EMT-associated genes to the abundance of intratumor microbes in MIBC patients, we found significant correlations between the abundance of microbes and either the upregulation or downregulation of EMT-associated genes. Our findings call for an investigation of possible mechanisms through which the microbiome may regulate EMT in MIBC patients. With further investigation, our findings can be used to provide a new, microbial approach in the diagnosis and therapy of MIBC.The intra-tumor microbiome has recently been linked to epithelial–mesenchymal transition (EMT) in a number of cancers. However, the relationship between EMT and microbes in bladder cancer has not been explored. In this study, we profiled the abundance of individual microbe species in the tumor samples of over 400 muscle invasive bladder carcinoma (MIBC) patients. We then correlated microbe abundance to the expression of EMT-associated genes and genes in the extracellular matrix (ECM), which are key players in EMT. We discovered that a variety of microbes, including E. coli, butyrate-producing bacterium SM4/1, and a species of Oscillatoria, were associated with expression of classical EMT-associated genes, including E-cadherin, vimentin, SNAI2, SNAI3, and TWIST1. We also found significant correlations between microbial abundance and the expression of genes in the ECM, specifically collagens and elastin. Lastly, we found that a large number of microbes exhibiting significant correlations to EMT are also associated with clinical prognosis and outcomes. We further determined that the microbes we profiled were likely not environmental contaminants. In conclusion, we discovered that the intra-tumoral microbiome could potentially play a significant role in the regulation of EMT in MIBC.

Neoadjuvant immunotherapy for muscle invasive urothelial bladder carcinoma: will it change current standards?

Immunotherapy, in the form of immune checkpoint inhibitors (ICI), has shown activity in metastatic urothelial bladder carcinoma, resulting in the approval of several ICI agents in the first- and second-line settings. This has led to an increased interest in studying their efficacy in the neoadjuvant setting for muscle invasive disease – an area of significant unmet need. This non-systematic review will look at the evidence supporting the use of ICI in the neoadjuvant setting for this tumor, results of early-phase studies, ongoing trials, and possible future applications for these drugs.