Urothelial Histology Research Articles

MP63-05 OUTCOMES IN PATIENTS (PTS) WITH BACILLUS CALMETTE-GUERIN (BCG)-UNRESPONSIVE HIGH-RISK (HR) NON-MUSCLE-INVASIVE BLADDER CANCER (NMIBC) WHO UNDERWENT RADICAL CYSTECTOMY (RC) FOLLOWING PEMBROLIZUMAB (PEMBRO) TREATMENT IN KEYNOTE-057 COHORT A

MP63-05 OUTCOMES IN PATIENTS (PTS) WITH BACILLUS CALMETTE-GUERIN (BCG)-UNRESPONSIVE HIGH-RISK (HR) NON-MUSCLE-INVASIVE BLADDER CANCER (NMIBC) WHO UNDERWENT RADICAL CYSTECTOMY (RC) FOLLOWING PEMBROLIZUMAB (PEMBRO) TREATMENT IN KEYNOTE-057 COHORT A

Pembrolizumab (pembro) monotherapy for patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette–Guérin (BCG): Results from cohort B of the phase 2 KEYNOTE-057 trial.

LBA442 Background: Although most pts with HR NMIBC respond to BCG, pts whose cancer does not respond or who relapse within 12 mo have poor prognosis and require radical cystectomy (RC). The single-arm, multicohort phase 2 KEYNOTE-057 trial (NCT02625961) was designed to investigate the safety and efficacy of pembro monotherapy for pts with BCG-unresponsive HR NMIBC (per FDA) who were ineligible or declined to undergo RC. Results from cohort A (carcinoma in situ [CIS] ± papillary tumors) showed a clinical complete response rate of 41% at 3 mo and led to approval of pembro monotherapy for such pts in the United States. We describe the results from cohort B (papillary tumors without CIS). Methods: Pts were aged ≥18 y with BCG-unresponsive HR NMIBC with papillary tumors only (high-grade Ta or any-grade T1) at baseline and ECOG PS 0-2. Pts received pembro 200 mg every 3 wk (Q3W) for ≤35 cycles (~2 y). Cancer was assessed at 12 wk and Q12W thereafter if no recurrent HR NMIBC or progression was observed; CT urography was done Q24W. Primary end points for cohort B were 12-mo disease-free survival (DFS) rate of HR NMIBC as assessed by central pathology/radiology review and safety, assuming a 12-mo DFS of >20% for HR NMIBC. Secondary efficacy end points were 12-mo DFS rate of any disease; progression-free survival (PFS) to worsening of grade, stage, or death; PFS to muscle invasion, metastasis, or death; and overall survival (OS). Results: Overall, 132 pts received pembro for a median of 9.5 cycles (range, 1.0-35.0). Median age was 72 y (range, 37-87); 57 pts (43.2%) had T1 stage; all pts (100%) had urothelial histology; 104 pts (78.8%) were male; pts received a median of 10 (range, 6-33) prior BCG instillations. Median follow-up was 45.4 mo (range, 14.9-77.1). Efficacy data are shown in Table. Thirty-one pts (23.5%) had RC after stopping pembro. Treatment-related AEs occurred in 97 pts (73.5%); 19 (14.4%) had a grade 3/4 treatment-related AE and 14 pts (10.6%) discontinued due to a treatment-related AE. No deaths from treatment-related AEs occurred. Conclusions: Pembro showed notable antitumor activity in pts with BCG-unresponsive non-CIS papillary HR NMIBC after ~45 mo of follow-up. Toxicity was manageable and consistent with that in cohort A, with no new safety signals. Results suggest pts with non-CIS papillary HR NMIBC unresponsive to BCG who declined or were ineligible to undergo RC may also benefit from pembro monotherapy. Clinical trial information: NCT02625961 . [Table: see text]

Multi-center, retrospective study of first-line systemic therapy ± immune checkpoint inhibition for metastatic neuroendocrine carcinoma of the urinary tract.

467 Background: Neuroendocrine, small cell, or large cell carcinoma originating from the urothelium (uro-NE/SCC/LCC) is rare. Outcomes for metastatic disease are dismal. Treatment is extrapolated from small cell lung cancer, for which immune checkpoint inhibitors (ICIs) have modest activity. Preliminary activity has been reported with ICI for uro-NE. We aimed to compare real-world progression-free survival (PFS) and overall survival (OS) between ICI-containing and non-ICI-containing regimens in the first line (1L) metastatic setting for uro-NE/SCC/LCC. Methods: We performed a retrospective study at 11 cancer centers. Patients (pts) who received systemic therapy (2011-2021) for biopsy confirmed metastatic uro-NE/SCC/LCC were included. Pts with metastasis within 6 months of (neo)adjuvant chemotherapy (CT) (n=16) were excluded from 1L analyses. Results: 102 pts with metastatic uro-NE/SCC/LCC were evaluable. 17 (16.7%) had NE histology, 81 (79.4%) SCC, and 4 (3.9%) LCC. NE/SCC/LCC was mixed with urothelial histology in 19 (18.6%). Primary tumors were most often in the bladder (84.3%, n=86), less frequently upper tract (11.8%, n=12) or urethra (3.9%, n=4). 42 pts (41.2%) were previously treated for localized disease, the rest were de novo metastatic (n=60, 58.8%). Pts who received an ICI in any line (n=61) had significantly longer OS (p=0.038) than pts that never received an ICI (n=41). As shown in the table, in the 1L, ICI-containing regimens (n=33) resulted in significantly longer PFS, but not OS or ORR compared to non-ICI regimens (n=53). Subdividing 1L regimens into ICI without CT (n=14), CT without ICI (n=53), or ICI + CT (n=19), both PFS and OS were significantly different with similar ORR. ICI w/o CT had the longest median PFS and OS with an ORR 57.1% comparable to CT regimens. Of 61 pts that received ICI in any line, 14 (23.0%) had an immune-related adverse event of any grade; 11 (18.0%) received steroids. Conclusions: This is the largest ever report of ICI for metastatic uro-NE/SCC/LCC. ICIs were associated with improved outcomes with expected added toxicity. Further prospective investigation of ICI regimens is warranted. [Table: see text]

Perioperative enfortumab vedotin (EV) plus pembrolizumab (pembro) versus chemotherapy in cisplatin-eligible patients (pts) with muscle-invasive bladder cancer (MIBC): Phase 3 KEYNOTE-B15/EV-304.

TPS588 Background: Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy + pelvic lymph node dissection (RC+PLND) is the standard of care for cisplatin-eligible pts with MIBC; however, up to 50% of pts will experience disease recurrence or progression following treatment. Pembro and EV monotherapies are approved for use in select pts with metastatic urothelial carcinoma (mUC). Furthermore, results of the phase 1/2 KEYNOTE-869/EV-103 study showed encouraging antitumor activity and an acceptable safety profile with first-line combination therapy EV + pembro in cisplatin-ineligible pts with mUC. The open-label, multicenter, phase 3, randomized KEYNOTE-B15/EV-304 study (NCT04700124) will compare the efficacy and safety of perioperative EV + pembro versus neoadjuvant cisplatin-based chemotherapy in cisplatin-eligible pts with MIBC. Methods: Eligible pts will have histologically confirmed UC/MIBC (T2-T4aN0M0 or T1-T4aN1M0) with predominant urothelial histology (≥50%), nonmetastatic disease (N≤1, M0) confirmed by blinded independent central review (BICR), ECOG performance status of 0-1, no prior systemic therapy for MIBC, and agree to undergo curative RC+PLND. Approximately 784 pts will be randomly assigned 1:1 to Arm A (4 cycles of neoadjuvant EV + pembro, followed by RC+PLND, followed by 5 cycles of adjuvant EV + 13 cycles of adjuvant pembro) or Arm B (4 cycles of neoadjuvant chemotherapy [gemcitabine + cisplatin] followed by RC+PLND, followed by observation). Neoadjuvant and adjuvant pembro 200 mg + EV 1.25 mg/kg will be administered intravenously every 3 weeks (Q3W) on day 1 (pembro + EV) and day 8 (EV) of each cycle. Neoadjuvant chemotherapy is gemcitabine 1000 mg/m2 + cisplatin 70 mg/m2 Q3W on day 1 (gemcitabine + cisplatin) and day 8 (gemcitabine) of each cycle. Stratification factors are disease stage (T2N0 vs T3/T4aN0 vs T1-T4aN1), PD-L1 combined positive score (≥10 vs <10), and geographic region (United States vs European Union vs most of the world). Imaging by CT (preferred) or MRI will be performed ≤6 weeks before cystectomy and 6 weeks after cystectomy. Imaging will occur following cystectomy then Q12W through year 2 and at discontinuation, then Q24W in year 3 and beyond. Adverse events (AEs) will be monitored throughout the study and for 30 days following cessation of treatment (90 days for serious AEs). The primary end points are pathologic complete response rate and event-free survival by BICR. Secondary end points are OS, DFS, pathologic downstaging rate, safety and tolerability, and patient-reported outcomes. KEYNOTE-B15/EV-304 is enrolling in Africa, Asia, Australia, Europe, and North America. © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved. Clinical trial information: NCT04700124 .

Biomarkers of response to enfortumab vedotin (EV) in patients (pts) with advanced urothelial carcinoma (aUC): Analysis of the UNITE study.

450 Background: EV, an antibody-drug conjugate (ADC) targeting Nectin-4, is used widely in treatment-refractory aUC, but limited data are available on biomarkers predictive of EV outcomes. We investigated potential biomarkers of response to EV in a pt cohort in the UNITE dataset. Methods: We included the retrospective UNITE study pts from 16 sites, with available next generation sequencing using institutional or commercial platforms, treated with EV alone outside clinical trials. Observed response (ORR) was determined by investigators for evaluable pts with scans after ≥1 dose of EV. Assessed molecular biomarkers included tumor mutation burden (TMB), PD-L1 status, somatic alterations (alts) in ≥ 10% of pts ( TERTp, TP53, ARID1A, CDKN2A, CDKN2B, FGFR3, ERBB2, CCND1, KDM6A, MTAP, PIK3CA, RB1, TSC1) and presence of ≥1 DNA damage response mutations ( ATM, BARD1, BRCA1, BRCA2, CDK12, CHEK2, PALB2, PPP2R2A, or RAD51B). ORRs were compared using Chi-squared test, while median progression-free and overall survival (mPFS, mOS) from EV start were compared with log-rank test and Cox proportional hazards in pts with and without biomarker presence. Results: A total of 170 pts had outcomes and NGS data available. Median age was 70, 133 (78%) were men, 144 (85%) Caucasian, 110 (65%) with pure urothelial histology, 118 (69%) with primary bladder tumor, and 116 (68%) had ≥ 2 lines of therapy before EV. For all pts, ORR 47%, mPFS 6 mos, mOS 12 mos. ORRs were higher in pts with ERBB2 (67% vs 44%; p = 0.05) and TSC1 (68% vs 25%; p=0.04) alts vs wild-type. Shorter mPFS was noted in pts with CDKN2A, CDKN2B, and MTAP alts, and longer mOS in pts with high TMB (table). Conclusions: This large, multi-site, retrospective cohort of pts with aUC identified several potential biomarkers associated with differential outcomes to EV. These findings, upon external validation, may help inform clinical decision making and potential therapy sequencing with available ADCs. Limitations include retrospective nature, pt selection, and confounding biases. [Table: see text]

Association of biomarkers and outcomes in patients (pts) with metastatic urothelial carcinoma (mUC) treated with immune checkpoint inhibitors (ICIs).

532 Background: ICIs form the backbone of treatment for mUC. However, only a minority of pts benefit and additional biomarkers of ICI response are needed. Methods: In our institution, we identified mUC pts treated with ICI monotherapy who had next generation sequencing (NGS). Somatic alterations present in ≥10% of pts ( ARID1A, CCND1, CDKN2A, CDKN2B, ERBB2, FGF3, FGF4, FGF19, FGFR3, KDM6A, MDM2, MLL2, PIK3CA, RB1, TERTp, TP53, TSC1), as well as DNA-damage response (DDR) alterations and tumor mutational burden (TMB) were analyzed as biomarkers. These biomarkers were individually evaluated in separate multivariate models while accounting for clinical factors including age, BMI, ECOG PS, primary tumor location, histology, hemoglobin, neutrophil to lymphocyte ratio and albumin. Multivariate cox regression and logistic regression models were used to measure hazard ratios (HR) and odds ratios (OR) for overall survival (OS), progression-free survival (PFS) and observed response rate (ORR). Results: Among 152 mUC ICI-treated pts, 107 had NGS data (FoundationOne, UCSF500, Strata), including 85 with TMB data. For the 107 pts with NGS, median age was 70 yrs, majority were male (69, 64%), Caucasian (70, 65%), had pure urothelial histology (57, 53%), and had first-line ICI (55, 51%). ORR was 35%, median PFS was 3.9 mos (95% CI: 2.6-7.5 mos), and median OS was 17.4 mos (95% CI: 14.1-30.6 mos). Biomarkers associated with improved outcomes to ICI, independent of relevant clinical factors, included alterations in ARID1A and DDR, as well as high TMB (>10 Mut/Mb). Inferior outcomes were seen in pts with CDKN2B, KDM6A, FGF3, FGF4, and FGF19 alterations (Table). Conclusions: In this large retrospective multivariate analysis controlling for clinical factors in ICI-treated mUC pts, we found multiple biomarkers associated with improved or inferior outcomes. These hypothesis-generating findings can inform clinical decision making and trial design for mUC pts treated with ICIs, and should be validated in larger cohorts. [Table: see text]

Benefit of whole-pelvis radiation for patients with muscle-invasive bladder cancer: An inverse probability treatment-weighted analysis.

449 Background: Pelvic lymph node irradiation is still under debate for patients with muscle-invasive bladder cancer (MIBC) planned for curative-intent radiation-based therapy (RT). A previous randomized trial suggested bladder-only (BO)-RT was effective in reducing RT-related toxicity, while associated with non-inferior oncological outcomes – bladder preservation rates, disease-free survival, and overall survival (OS) – compared to whole-pelvis (WP)-RT. In this study, we sought to evaluate the impact of the radiation volume (BO-RT vs. WP-RT) on main oncological outcomes in patients with MIBC. Methods: This nationwide study included patients with urothelial MIBC (cT2-4aN0-2M0) who underwent curative RT at 10 academic centers across Canada. Patients clinically staged with pelvic or abdominal wall invasion (cT4b) or enlarged lymph nodes beyond the common iliac bifurcation (cN3) before RT were excluded. Patients were divided into two groups based on the RT volume: WP-RT vs. BO-RT. Inverse probability of treatment weighting (IPTW) and absolute standardized differences (ASDs) were used to balance baseline covariates across treatment groups. Regression models were used to assess the impact of the RT volume on the rates of complete response (CR) to treatment, cancer-specific survival (CSS), and OS while adjusting for potential confounding variables in the weighted cohorts. Results: A total of 599 patients were analyzed, out of whom 369 (61.6%) underwent WP-RT. Patients in the WP-RT group were younger (mean age 73.2 vs. 77.4; ASD 0.41), and more likely to have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 (82.1% vs. 73.5%; ASD 0.21), clinical node-positive disease (12.5% vs. 2.2%; ASD 0.40), and lymphovascular invasion (26.3% vs. 16.1%; ASD 0.25), compared to BO-RT. In addition, WP-RT patients were more commonly treated with neoadjuvant chemotherapy (20.9% vs. 10.4%; ASD 0.29) and concurrent chemotherapy (76.7% vs. 56.5%; ASD 0.44), compared to BO-RT. In the IPTW cohort, age, gender, ECOG PS, clinical staging, the proportion of patients with carcinoma in situ, lymphovascular invasion, variant urothelial histologies, hydronephrosis, and whose tumours were completely resected before RT, treated with NAC, and treated with concurrent chemotherapy were well balanced across groups (all ASDs < 0.10). In multivariable analysis, WP-RT did not impact CR rates post-RT (OR 1.14; p=0.526) but was associated with both CSS (HR 0.66; p=0.016) and OS (HR 0.68; p=0.002), independently of other prognostic factors (Table). Conclusions: Our study demonstrated a significant survival benefit with the use of WP-RT compared to BO-RT in patients with MIBC treated with curative intent. Additional randomized controlled trials are needed to confirm our findings.

Association of biomarkers and response to immune checkpoint inhibitors (ICIs) in patients with metastatic urothelial carcinoma (mUC) with high and low tumor mutation burden (TMB).

534 Background: ICIs are frequently used as therapy in mUC, but only a minority of patients (pts) respond to treatment. High TMB is associated with improved outcomes to ICIs. However, much is unknown about biomarkers associated with ICI outcomes in pts with high and low TMB respectively. Methods: We retrospectively identified mUC pts with known TMB status and available next generation sequencing (NGS) results treated with ICI monotherapy at our institution. TMB high was defined as ≥ 10 mutations/Mb, with the rest being TMB low. Somatic alterations present in ≥10% pts ( ARID1A, CCND1, CDKN2A, CDKN2B, ERBB2, FGF3, FGF4, FGF19, FGFR3, KDM6A, MDM2, MLL2, PIK3CA, RB1, TERTp, TP53, TSC1), and presence of DNA damage response (DDR) alterations were assessed as biomarkers of interest. Within the TMB-high and TMB-low pt groups we separately assessed patients based on the presence or absence of these somatic alterations, APOBEC mutational signature and high PD-L1 expression. Log rank test was used to determine differences in overall survival (OS) and progression free survival (PFS) among these groups. P-value ≤0.05 was considered significant. Results: Among 107 mUC pts treated with ICI monotherapy between 12/2014 and 3/2022 who had NGS data (UCSF500, FoundationOne, Strata), 85 pts had TMB data, including 47 TMB high pts and 38 TMB low pts. Among 85 pts with known TMB status, median age was 76 yrs, the majority were male (55, 65%), Caucasian (57, 67%), had pure urothelial histology (46, 55%) and were treated with ICIs in frontline setting (47, 55%). Median OS was 17.2 mos and median PFS was 3.42 mos. In TMB high pts, presence of DDR , MLL2, KDM6A, PIK3CA and TERTp alterations were each associated with improved outcomes, while presence of CDKN2B alterations was associated with inferior outcomes (Table). Among TMB low pts, those with RB1 alterations had shorter mOS (11.3 months vs 17.2 months; p=0.04) compared to wild-type pts. Conclusions: In this single-center retrospective analysis of mUC pts, we identified somatic alterations that were predictive of outcomes with ICI treatment in TMB high and TMB low pts respectively. Further exploration of biomarkers in patients stratified by TMB status is warranted in larger cohorts. [Table: see text]

Challenges and opportunities in the management of non-urothelial bladder cancers

Urothelial carcinoma accounts for approximately 90% of all bladder cancer diagnoses. Localized, muscle-invasive disease is often managed with a multidisciplinary approach including either neoadjuvant chemotherapy (NAC) followed by radical cystectomy or concurrent chemoradiation, whereas multiple immunotherapies and novel antibody drug conjugates have recently joined platinum-based chemotherapy as standard of care therapy for metastatic disease. However, the clinical trials leading to these standards often require majority if not complete urothelial histology for eligibility. As many as one quarter of patients diagnosed with bladder cancer will have either divergent differentiation of their urothelial carcinoma or an alternate epithelial tumor such as squamous cell carcinoma, adenocarcinoma, or small cell carcinoma; even more rare are non-epithelial tumors such as sarcoma. The rarity of these diseases and their general exclusion from treatment within prospective clinical trials has created a challenging situation where treatment plans are often derived from case series or extrapolated from other disease types and outcomes are poor compared to pure urothelial carcinoma. In this review, we summarize the existing data on the diagnosis and treatment of epithelial, non-urothelial bladder cancers including adenocarcinoma, squamous cell carcinoma, and small cell carcinoma in their localized and advances stages. We will also review the current clinical trial landscape investigating novel approaches to these diseases.

Preliminary efficacy of [90Y]DOTA-biotin-avidin radiotherapy against non-muscle invasive bladder cancer.

Bladder cancer represents 3% of all new cancer diagnoses per year. We propose intravesical radionuclide therapy using the β-emitter 90Y linked to DOTA-biotin-avidin ([90Y]DBA) to deliver short-range radiation against non-muscle invasive bladder cancer (NMIBC). Image-guided biodistribution of intravesical DBA was investigated in an animal model by radiolabeling DBA with the 68Ga and dynamic microPET imaging following intravesical infusion of [68Ga]DBA for up to 4h and post-necropsy γ-counting of organs. The antitumor activity of [90Y]DBA was investigated using an orthotopic MB49 murine bladder cancer model. Mice were injected with luciferase-expressing MB49 cells and treated via intravesical administration with 9.2MBq of [90Y]DBA or unlabeled DBA 3days after the tumor implantation. Bioluminescence imaging was conducted after tumor implantation to monitor the bladder tumor growth. In addition, we investigated the effects of [90Y]DBA radiation on urothelial histology with immunohistochemistry analysis of bladder morphology. Our results demonstrated that DBA is contained in the bladder for up to 4h after intravesical infusion. A single dose of [90Y]DBA radiation treatment significantly reduced growth of MB49 bladder carcinoma. Attaching 90Y-DOTA-biotin to avidin prevents its re-absorption into the blood and distribution throughout the rest of the body. Furthermore, immunohistochemistry demonstrated that [90Y]DBA radiation treatment did not cause short-term damage to urotheliumat day 10, which appeared similar to the normal urothelium of healthy mice. Our data demonstrates the potential of intravesical [90Y]DBA as a treatment for non-muscle invasive bladder cancer.

Dietary Capsaicin Reduces Chemically Induced Rat Urinary Bladder Carcinogenesis.

Capsaicin (CAP) is the compound responsible for pungency in chili peppers, presenting several biological properties. But its general safety and effectiveness in the context of carcinogenesis has not been fully clarified. Thus, the present study evaluated whether dietary CAP modifies the development of urothelial lesions induced by the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in male Sprague-Dawley rats. Animals were randomly allocated into 6 groups: G1 - treated with 0.05% BBN in drinking water (weeks 1-12) and received a balanced diet (weeks 1-20); G2 and G3-treated with BBN (weeks 1-12) and received a balanced diet with 0.01 or 0.02% CAP (weeks 1-20), respectively; G4 and G5- only received a balanced diet with 0.01 or 0.02% CAP (weeks 1-20), respectively; G6 - only received a balanced diet (weeks 1-20). At the end of week 20, the incidence and types of urothelial lesions, proliferating cell nuclear antigen (PCNA) labeling index, and matrix metalloproteinases (MMP) 2 and 9 activities were analyzed. A significant reduction was observed in the incidence and multiplicity of simple (p = 0.020 and p = 0.011) and nodular/papillary (p = 0.030 and p = 0.003) hyperplasias and papillomas/carcinomas (p = 0.023 and p = 0.020), epithelial proliferation (p = 0.007) and in the activity of the intermediate form of MMP-2 (p < 0.001) and pro-MMP-9 activities (p < 0.002), in BBN + 0.02% CAP (G3) group in comparison to BBN (G1) group. Capsaicin intake per se did not alter body weight, liver and kidney weights, urothelial histology or serum biochemical parameters. Thus, dietary CAP was safe and showed a protective effect against rat BBN-induced urothelial carcinogenesis.

Chemotherapy with significant mortality benefit in patients with bladder cancer with variant and non-urothelial histologies (NUVH).

4586 Background: Non urothelial cancers and urothelial cancers with variant histologies(NUVH) have a more aggressive natural history and are at a higher risk of progression to muscle invasive disease(MIBC) when compared to their urothelial counterparts. Although surgical resection is the treatment of choice in localized disease, radiation(RT) is commonly used in patients who are not surgical candidates. The use of chemotherapy has shown modest benefit in some retrospective studies. Considering the low incidence of NUVH, there are no large-scale studies examining the benefits of chemoradiation(CRT) in MIBC with NUVH. Methods: The National Cancer Database was queried to identify MIBC patients with NUVH from the years 2004-2018.Inclusion criteria for the study are age &gt; 18 years, Non urothelial or variant histologies and receipt of RT. Patients who underwent cystectomy or had metastatic disease were excluded. The population was divided into two cohorts if they received chemoradiation. Chi-Square test and Mann Whitney U tests were used to compare frequency distributions. Cox proportional Hazard regression was employed to control for confounding factors associated with overall survival. Covariates for confounding included age, race, sex, income, insurance status, charlson-deyo comorbidity index, education. Results: Among 1773 observations in the final analysis, 63.05%(n = 1118) received CRT. Small cell, large cell and neuroendocrine cancers composed of the majority of NUVH. 38.01% (n = 641). Other histologies composed of squamous cell cancer 30.34%(n = 538), spindle cell/sarcomatoid cancers10.15%(180), adenocarcinoma 11.44%(203). Patients who received CRT were found to be significantly younger (76 vs 82 years P: &lt; 0.0001) with higher male predominance74.73%. 5 year overall mortality was significaantly lower in the CRT vs RT group ( 66.47% vs 81.55%, p &lt; 0.001). After controlling for confounding factors, CRT was associated with lower risk of mortality Hazard Ratio(HR)of 0.41(0.36-0.47) p &lt; 0.0001. Added, the survival benefit of CRT continued in the non small cell variant cohort HR: 0.43(0.37-0.51) P &lt; 0.0001. Conclusions: In this large retrospective study, CRT was associated with reduced overall mortality among patients with non-urothelial MIBC. The findings suggest the importance of systemic therapy in providing a survival advantage to non-urothelial MIBC, including the non-small cell variants. [Table: see text]

Phase I study of intravesical anti-CD40 agonist antibody 2141-V11 for non-muscle invasive bladder cancer unresponsive to Bacillus Calmette-Guerin (BCG) therapy.

TPS4616 Background: CD40 is an immune-stimulatory receptor centrally involved in activating antigen-presenting cells and downstream anti-tumor immunity. Multiple agonistic anti-CD40 antibodies have been investigated clinically for cancer therapy, but have thus far shown limited efficacy and notable systemic toxicity. Our group has previously demonstrated that the ability of the Fc domain of anti-CD40 agonist antibodies to engage the FcγRIIB receptor, needed for optimal CD40 crosslinking, is critical for CD40 agonist activity. We engineered a fully-human anti-CD40 agonist antibody (2141-V11) with optimized Fc binding to FcγRIIB, which demonstrates significantly enhanced CD40 agonist activity. Non-muscle invasive bladder cancer (NMIBC), which remains an area of significant unmet need, represents an attractive clinical context to pursue CD40 agonist therapy given strong enrichment of CD40 in the bladder tumor microenvironment and routine use of local intravesical delivery as a potential strategy to mitigate systemic toxicity. Our preclinical studies, including in immunocompetent orthotopic murine models of bladder cancer humanized for CD40 and Fcγ receptors, revealed that intravesical delivery of 2141-V11 induced potent and durable anti-tumor immunity in both front-line and BCG-unresponsive settings without associated systemic toxicity (Garris and Wong, et al., Sci Transl Med, 2021;13:eabd1346). These data provide rationale to investigate intravesical 2141-V11 for the treatment of BCG-unresponsive NMIBC. Methods: This is a phase 1, open-label, dose-escalation study (NCT05126472) to evaluate the safety and tolerability of intravesically-delivered 2141-V11 in patients with BCG-unresponsive NMIBC who are considered ineligible for or have elected not to undergo radical cystectomy. Key inclusion criteria include adults with high-grade NMIBC (Ta, CIS, and/or T1) of urothelial histology that is unresponsive to adequate BCG therapy per consensus 2018 FDA guidelines. The primary objectives are to evaluate the safety and tolerability of 2141-V11 and to define the maximum tolerated dose and/or recommended phase 2 dose. The secondary objectives are to characterize the pharmacokinetics and evaluate the preliminary clinical activity of 2141-V11. Exploratory objectives include assessment of biomarkers of biological activity and disease resistance, their potential associations with clinical outcome measures, and patient-reported outcomes/quality of life measures. The 2141-V11 antibody is administered intravesically once weekly for 3 doses. Depending on disease status at week 13 and week 25 evaluations, patients may be eligible for re-treatment (once weekly for 3 doses) at these time points. Dose exploration utilizes a modified continual reassessment method design. Enrollment began in November 2021 and is ongoing. Clinical trial information: NCT05126472.

Association Between Perioperative Chemotherapy and Survival in Men Undergoing Radical Resection for Primary Urethral Urothelial Carcinoma: An Analysis of the National Cancer Database.

The treatment landscape in invasive primary carcinoma of the urethra of urothelial histology closely aligns that of locally advanced urothelial carcinoma of the bladder. The survival benefit of perioperative chemotherapy for men undergoing radical surgery for primary urethral urothelial carcinoma (UUC) has not yet been well-elucidated. Using the National Cancer Database (NCDB), we identified men diagnosed with non-metastatic invasive UUC (T2-4 N0-2 M0) from 2004 to 2016 treated with radical extirpative surgery. We compared OS between patients who had received peri-operative neoadjuvant (NAC) or adjuvant (AC) chemotherapy and those who had not using Kaplan-Meier curves and multivariable Cox proportional hazards regression model. A total of 191 patients met inclusion criteria. 113 patients (59.2%) did not receive chemotherapy, while 39 (20.4%) and 39 (20.4%) received NAC and AC, respectively. Median follow-up was 28.0 months. Upon multivariable analysis, receipt of NAC (HR 0.50, 95% CI 0.28-0.91, P=.02) decreased the risk of all-cause mortality, while receipt of AC (HR 0.76, 95% CI 0.41-1.41) was not significantly associated with an OS benefit, as compared to no chemotherapy. Our study is the first to evaluate treatment specific outcomes in male patients with primary carcinoma of the urethra. We observed that neoadjuvant chemotherapy in men with UUC was associated with OS benefit. The utilization of NAC may improve survival, consistent with urothelial carcinoma of the bladder.

Outcomes by time to definitive chemoradiation treatment for patients with muscle-invasive bladder cancer.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has raised concerns about delaying treatment for localized cancer and its impact on long-term outcomes.ObjectiveWe aimed to investigate the impact of time to chemoradiation (CRT) on recurrence and survival outcomes for patients with muscle-invasive bladder cancer (MIBC).MethodsIn the national Veterans Affairs’ database, we identified patients with urothelial histology, MIBC (T2-4a/N0-3/M0) diagnosed between 2000 to 2018 and treated with definitive CRT. Time to treatment was defined as the number of days between date of diagnosis and start date of CRT. The cohort was stratified into < 90 (early) or ≥ 90 days (delayed) groups. Endpoints of locoregional failure (LRF), distant failure (DF), overall survival (OS), and bladder cancer-specific survival (BCS) were evaluated in multivariable Cox and Fine-Gray models.Results305 patients with MIBC underwent CRT – 190 (62.3%) received early CRT, 115 (37.7%) received delayed CRT. Multivariable analysis (including success of transurethral resection of bladder tumor and type of chemotherapy) revealed no difference in recurrence between groups – LRF HR 1.12 (95%CI 0.76-1.67, P = 0.56) and DF HR 1.03 (95%CI 0.70-1.53, P = 0.88). Similarly, there were no differences in survival outcomes. The lack of association was maintained at both earlier and later time cutoffs (60–120 days).ConclusionsOur findings suggest that a short-term delay in definitive therapy may not affect long-term outcomes for patients with MIBC undergoing CRT. This study does not endorse delays in therapy, but rather provides information to aid patients and clinicians navigate the unique challenges of MIBC care in both pandemic and non-pandemic times.

Impact of selection bias on outcomes in veterans with muscle-invasive bladder cancer receiving bladder preserving trimodality therapy.

462 Background: Retrospective studies using large registries comparing outcomes between radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) to trimodality therapy (TMT), which includes transurethral resection of bladder tumor followed by chemoradiation, often cannot distinguish whether patients receiving TMT were eligible for cystectomy but declined or simply ineligible for cystectomy. The objective of this study was to compare survival outcomes of patients with MIBC receiving TMT stratified by whether they were cystectomy-eligible to patients receiving RC +/- NAC. Methods: We used the national Veterans Affairs’ (VA) database to identify patients diagnosed between 2000-2017 with urothelial histology, MIBC (T2-4a/N0-3/M0) who underwent RC or TMT. Overall survival (OS) was evaluated with multivariable Cox proportional hazards model. Bladder cancer-specific mortality (BCSM) was evaluated with multivariable Fine-Gray regression. We conducted a chart review of clinical notes to ascertain if patients were eligible for cystectomy. Results: Overall 2306 Veterans with MIBC were included: 1472 (64%) with RC without NAC, 506 (22%) with RC-NAC, 107 (4.6%) with TMT eligible for RC, and 221 (9.4%) with TMT ineligible for RC. Median follow up time was 4.7 years. Patients receiving RC were on average 10 years younger, had higher creatinine clearance, and fewer comorbidities than those receiving TMT. Cystectomy-eligible TMT patients had higher creatinine clearance and fewer comorbidities than those ineligible for cystectomy. On multivariable analysis, compared to RC-NAC, TMT in cystectomy-eligible patients was associated with similar OS (hazard ratio [HR] 0.99; 95% confidence interval [CI] 0.76 - 1.28; p = 0.93) and BCSM (HR 1.02; 95% CI 0.71-1.47; p = 0.91). Compared to RC-NAC, TMT in cystectomy-ineligible patients was associated with inferior OS (HR 1.39; 95% CI 1.13 - 1.71; p = 0.002) and BCSM (HR 1.61; 95% CI 1.23 - 2.10; p &lt; 0.001). Conclusions: There is a significant selection bias among patients with MIBC receiving TMT. Cystectomy-eligible patients receiving TMT likely have similar survival outcomes as those receiving RC. Comparisons between RC and TMT in large registry data that lack information regarding eligibility for cystectomy in the TMT arm may be unreliable.

Biomarkers predictive of response to enfortumab vedotin (EV) treatment in advanced urothelial cancer (aUC).

531 Background: EV is an antibody-drug conjugate which recently received full FDA approval for treatment-refractory aUC. Molecular biomarkers and characteristics of patients (pts) most likely to respond to EV therapy have not been well defined. Methods: We retrospectively identified all aUC pts treated with EV at our institution. Clinicopathologic, treatment and response data were abstracted from pt charts. Pts were considered responders to EV if they had a complete response on initial scans after 2-3 months of treatment, or were treated with EV for ≥ 6 months. Responders and non-responders were compared in terms of their molecular and clinical characteristics using Chi-squared test. Most common somatic alterations present in ≥10 pts ( TERTp, TP53, CDKN2A, CDKN2B) were also used to divide pts with available next-generation sequencing (NGS) results into groups with and without these alterations. Log rank test was used to determine differences in overall survival (OS) and progression free survival (PFS) among these groups. Results: Between 1/2020 and 8/2021 a total of 32 pts received EV and 28 had NGS data available with either FoundationOne (14 pts), UCSF500 (13 pts) or Strata (1). Median age was 69.5 years, 24 (75%) were male, 22 (69%) Caucasian, 22 (69%) had pure urothelial histology and 22 (69%) primary tumor location in the bladder. At EV start, 24 (75%) had visceral metastases (mets), 8 (25%) had liver mets, and 13 (41%) had bone mets. Median follow-up from EV start was 12.5 months (range 0.5-36); 20 (63%) pts received EV monotherapy, and 12 (37%) received EV as part of a combination regimen. Non-responders were more likely to have bone metastases (69% vs 21%, p&lt;0.01), but were otherwise similar in baseline clinical characteristics to responders. TP53 alterations were enriched in responders relative to non-responders, whereas non-responders had more CDKN2B alterations (Table). Similar findings were seen in the subset of pts treated with EV monotherapy. Pts with TP53 alterations had longer OS (NR vs 17.0 months, p=0.06) and PFS (NR vs 6.6 months, p=0.04) relative to wild-type pts. Shorter PFS was seen in pts with CDKN2A (4.4 months vs NR, p=0.05) and CDKN2B (4.3 months vs NR, p=0.02) alterations, but no differences in OS were observed. Conclusions: In this retrospective cohort of aUC pts with available NGS data, presence of TP53 and absence of CDKN2A and CDKN2B alterations were associated with favorable responses and improved clinical outcomes with EV, suggesting they may be biomarkers of response to EV. These preliminary findings should be validated in larger cohorts.[Table: see text]

Association of time to second-line (2L) immune-checkpoint inhibitors (ICI) and outcomes with ICIs in patients (pts) with advanced urothelial carcinoma (aUC).

505 Background: Current standard therapy for most pts with aUC is first-line (1L) platinum-based chemotherapy followed by ICI maintenance (or 2L if progression). Shorter time on 1L or between therapy lines may be a surrogate of more aggressive disease and poor outcome, but its prognostic role in ICI response is unclear. We hypothesized that shorter time until start of 2L ICI would be associated with worse outcomes in aUC. Methods: We performed a retrospective multi-institution cohort study in pts with aUC treated with 1L platinum-based chemotherapy, who later received 2L ICI. Pts receiving maintenance ICI were excluded. We calculated the time from start of 1L platinum chemotherapy to start of 2L ICI, dichotomizing the exposure into ≤6 months and &gt;6 months. We compared overall response rate (ORR) to 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI between the two populations. ORR was compared among groups using multivariable logistic regression and PFS, OS using cox regression. Analysis was adjusted for calculated Bellmunt score. Results: From a total of 1283 pts, 462 received 1L platinum chemotherapy; among those, 350 received 2L ICI. After exclusions, 270, 269 and 260 pts were included in the ORR, PFS and OS analyses, respectively. Median age was 70 years, 78% men, 75% White, 74% with pure urothelial histology, 21% upper tract, 60% received cisplatin in 1L. Pts with time to 2L ICI ≤6 months had significantly higher Bellmunt scores (32% vs 22% score=2, 9% vs 3% score=3). ORR and PFS were comparable between pts with ≤ and &gt;6 months to 2L ICI. However, OS was significantly longer for pts with &gt;6 months to 2L ICI (median [m]OS 13 vs 7 months, p=0.002), (Table). Conclusions: Among pts with aUC treated with 2L ICI, time to 2L ICI ≤6 months from 1L platinum based chemotherapy was associated with similar ORR and PFS but shorter OS. Limitations include retrospective nature, patient selection, confounding factors. More studies are needed on the impact of platinum resistance in pts with aUC treated with ICIs.[Table: see text]

Efficacy of enfortumab vedotin in advanced urothelial cancer: Analysis from the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study.

Enfortumab vedotin (EV) is a novel antibody-drug conjugate approved for advanced urothelial cancer (aUC) refractory to prior therapy. In the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study, the authors looked at the experience with EV in patient subsets of interest for which activity had not been well defined in clinical trials. UNITE was a retrospective study of patients with aUC treated with recently approved agents. This initial analysis focused on patients treated with EV. Patient data were abstracted from chart reviews by investigators at each site. The observed response rate (ORR) was investigator-assessed for patients with at least 1 post-baseline scan or clear evidence of clinical progression. ORRs were compared across subsets of interest for patients treated with EV monotherapy. The initial UNITE analysis included 304 patients from 16 institutions; 260 of these patients were treated with EV monotherapy and included in the analyses. In the monotherapy cohort, the ORR was 52%, and it was >40% in all reported subsets of interest, including patients with comorbidities previously excluded from clinical trials (baseline renal impairment, diabetes, and neuropathy) and patients with fibroblast growth factor receptor 3 (FGFR3) alterations. Progression-free survival and overall survival were 6.8 and 14.4 months, respectively. Patients with a pure urothelial histology had a higher ORR than patients with a variant histology component (58% vs 42%; P = .06). In a large retrospective cohort, responses to EV monotherapy were consistent with data previously reported in clinical trials and were also observed in various patient subsets, including patients with variant histology, patients with FGFR3 alterations, and patients previously excluded from clinical trials with an estimated glomerular filtration rate < 30 mL/min and significant comorbidities. Enfortumab vedotin, approved by the Food and Drug Administration in 2019, is an important new drug for the treatment of patients with advanced bladder cancer. This study looks at the effectiveness of enfortumab vedotin as it has been used at multiple centers since approval, and focuses on important patient populations previously excluded from clinical trials. These populations include patients with decreased kidney function, diabetes, and important mutations. Enfortumab vedotin is effective for treating these patients. Previously reported clinical trial data have been replicated in this real-world setting, and support the use of this drug in broader patient populations.

Treatment Discontinuation in Patients With Muscle-Invasive Bladder Cancer Undergoing Chemoradiation

PurposeChemoradiation (CRT) is a definitive treatment option for muscle-invasive bladder cancer (MIBC). Despite its effectiveness, CRT is underused, in part owing to concerns of tolerability and the need for integrated multidisciplinary care. We investigated factors associated with and the impact of treatment discontinuation in patients with MIBC treated with CRT. Methods and MaterialsIn the US Veterans Affairs’ national database, we identified patients with urothelial histology, MIBC (T2-4a/N0-3/M0) diagnosed between 2000 and 2018 and treated with definitive-intent CRT. The primary endpoint of discontinued radiation was evaluated in a multivariable logistic regression. Secondary endpoints of 30-day and 90-day mortality, overall mortality, and nonbladder cancer mortality were evaluated in multivariable models. ResultsOf 369 veterans with MIBC who underwent CRT, 30 patients (8.1%) did not complete radiation. The most common reasons for treatment discontinuation included comorbidities or infections necessitating hospital admission (63.3%) and treatment intolerance or declining performance status (26.7%). In multivariable logistic regression, variables associated with radiation discontinuation were creatinine clearance ≤ 50 (odds ratio [OR], 3.93; 95% CI, 1.63-9.50; P = .002), incomplete transurethral resection of bladder tumor (TURBT) (OR, 3.16; 95% CI, 1.15-8.63; P = .02), and nonpreferred chemotherapy (OR, 3.31; 95% CI, 1.31-8.36; P = .01). In the cohort that discontinued radiation, 30-day mortality was 33.3% and 90-day mortality was 50.0%, with the majority of deaths attributed to nonbladder cancer causes. No patient or tumor variables were associated with either endpoint. In the cohort that completed radiation, 30-day mortality was 2.7% and 90-day mortality was 6.8%. In multivariable analysis, radiation discontinuation was associated with worse overall mortality (hazard ratio [HR], 2.48; 95% CI, 1.36-4.50; P = .003) and worse nonbladder cancer mortality (HR, 2.32; 95% CI, 1.24-4.34; P = .008). ConclusionsWith a low rate of treatment discontinuation, CRT is an effective and feasible treatment option for the typically elderly and comorbid population of patients with MIBC. In addition to identified predictors of treatment discontinuation (poor renal function, incomplete TURBT, etc.), further research is required to develop evidence-based guidelines for optimal patient selection.