High-grade Ta Research Articles

Predicting Response to Intravesical BCG in High-Risk NMIBC Using an Artificial Intelligence-Powered Pathology Assay: Development and Validation in an International 12-Center Cohort.

There are few markers to identify those likely to recur or progress after treatment with intravesical bacillus Calmette-Guérin (BCG). We developed and validated artificial intelligence-based histologic assays that extract interpretable features from transurethral resection of bladder tumor digitized pathology images to predict risk of recurrence, progression, development of BCG-unresponsive disease, and cystectomy. Pre-BCG resection-derived whole-slide images and clinical data were obtained for high-risk NMIBC cases treated with BCG from 12 centers and were analyzed through a segmentation and feature extraction pipeline. Features associated with clinical outcomes were defined and tested on independent development and validation cohorts. Cases were classified into high or low risk for recurrence, progression, BCG-unresponsive disease, and cystectomy. Nine hundred forty-four cases (development: 303, validation: 641, median follow-up: 36 months) representative of the intended use population were included (high-grade Ta: 34.1%, high-grade T1: 54.8%; carcinoma in situ only: 11.1%, any carcinoma in situ: 31.4%). In the validation cohort, "high recurrence risk" cases had inferior high-grade recurrence-free survival vs "low recurrence risk" cases (HR, 2.08, P < .0001). "High progression risk" patients had poorer progression-free survival (HR, 3.87, P < .001) and higher risk of cystectomy (HR, 3.35, P < .001) than "low progression risk" patients. Cases harboring the BCG-unresponsive disease signature had a shorter time to development of BCG-unresponsive disease than cases without the signature (HR, 2.31, P < .0001). AI assays provided predictive information beyond clinicopathologic factors. We developed and validated AI-based histologic assays that identify high-risk NMIBC cases at higher risk of recurrence, progression, BCG-unresponsive disease, and cystectomy, potentially aiding clinical decision making.

Prognostic significance of residual tumor at restaging transurethral bladder resection in high-risk non-muscle-invasive bladder cancer.

To assess prognostic significance of residual tumor at repeat transurethral resection (reTUR) in contemporary non-muscle-invasive bladder cancer (NMIBC) patients. Patients were identified retrospectively from eight referral centers in France, Italy and Spain. The cohort included consecutive patients with high or very-high risk NMIBC who underwent reTUR and subsequent adjuvant BCG therapy. A total of 440 high-risk NMIBC patients were screened, 29 (6%) were upstaged ≥ T2 at reTUR and 411 were analyzed (T1 stage: n = 275, 67%). Residual tumor was found in 191 cases (46%). In patients with T1 tumor on initial TURBT, persistent T1 tumor was found in 18% of reTUR (n = 49/275). In patients with high-grade Ta tumor on initial TURBT, T1 tumor was found in 6% of reTUR (n = 9/136). In multivariable logistic regression analysis, we found no statistical association between the use of photodynamic diagnosis (PDD, p = 0.4) or type of resection (conventional vs. en bloc, p = 0.6) and the risk of residual tumor. The estimated 5-yr recurrence and progression-free survival were 56% and 94%, respectively. Residual tumor was significantly associated with a higher risk of recurrence (p < 0.001) but not progression (p = 0.11). Only residual T1 tumor was associated with a higher risk of progression (p < 0.001) with an estimated 5-yr progression-free survival rate of 76%. ReTUR should remain a standard for T1 tumors, irrespective of the use of en bloc resection or PDD and could be safely omitted in high-grade Ta tumors. Persistent T1 tumor at reTUR should not exclude these patients from conservative management, and further studies are needed to explore the benefit of a third resection in this subgroup.

Optimal Management for Primary High Grade Ta Bladder Cancer: Role of re-staging TURBT and Intravesical Adjuvant Therapy.

This study aims to investigate the impact of risk group classification, restaging transurethral resection (re-TURBT), and adjuvant treatment intensity on recurrence and progression risks in high-grade Ta tumours in patients with non-muscle invasive bladder cancer (NMIBC). Data from a comprehensive bladder cancer database were utilized for this study. Patients with primary high-grade Ta tumours were included. Risk groups were classified according to AUA/SUO criteria. Tumour characteristics and patient demographics were analysed using descriptive statistics. Cox proportional hazard regression models were used to assess the effect of re-TURBT and other clinical/treatment-related predictors on recurrence- and progression-free survivals. The survivals by selected predictors were estimated using Kaplan-Meier method, and groups were compared by the log-rank test. Among 218 patients with high-grade Ta bladder cancer, those who underwent re-TURBT had significantly better 5-year recurrence-free survival (71.1% vs. 26.8%, p = 0.0009) and progression-free survival (98.6% vs. 73%, p = 0.0018) compared with those with initial TURBT alone. Full BCG treatment (induction and maintenance) showed lower recurrence risk, especially in high-risk patients. However, residual disease at re-TURBT did not significantly affect recurrence risk. This study highlights the significance of risk group classification, the role of re-TURBT, and the intensity of adjuvant treatment in the management of high-grade Ta tumours. A risk-adapted model is crucial to reduce the burden of unnecessary intravesical treatment and endoscopic procedures.

Does Ta Low-grade Urothelial Carcinoma of the Bladder With Focal High-grade Features Carry Worse Prognosis? The Roswell Park Comprehensive Cancer Center Experience

ObjectivesTo describe the management and outcomes of patients with Ta predominantly low-grade urothelial carcinoma with focal high-grade features (FHG) (<5%), compared to those with Ta low grade (LG) and Ta high grade (HG). MethodsRetrospective review of all patients who underwent transurethral resection of bladder tumor (TURBT) between 2005 and 2023. Patients with Ta disease were identified and categorized into LG, FHG, and HG. Kaplan Meier method was used to depict high-grade recurrence, T-stage progression, and radical cystectomy-free survival. Results449 patients with Ta disease were identified (LG 48%, FHG 12%, and HG 40%). Patients with FHG (32%) had a second-look TURBT more frequently compared to LG (7%) and HG (29%) (p<0.01). They received intravesical therapy more frequently compared to LG (36% vs 20%) but lower than HG (55%) (p<0.01). They received radical cystectomy less frequently (7% compared to 20% for HG and 11% for LG, p=0.01). HG recurrence-free survival at 1, 3, and 5 years was HG (68%, 52%, and 43%), FHG (74%, 53%, and 49%), and LG (87%, 79%, and 73%) (log-rank p<0.01). T progression-free survival at 1, 3, and 5 years was HG (84%, 77%, and 70%), FHG (92%, 82%, and 82%), and LG (94%, 89%, and 85%) (log-rank p=0.02). Cystectomy-free survival at 1, 3, and 5 years was HG (92%, 84%, and 80%), FHG (96%, 94%, and 94%), and LG (99%, 95%, and 92%) (log-rank p<0.01) ConclusionPatients with Ta FHG seem to behave more like Ta HG disease in terms of high-grade recurrences, but they are less likely to experience T stage progression and convert to cystectomy.

Early experience with sequential intravesical gemcitabine and docetaxel for micropapillary variant non-muscle invasive bladder cancer

BackgroundGuidelines lack clear recommendations regarding conservative management of micropapillary (MP) variant non-muscle invasive bladder cancer (NMIBC). Bladder-sparing therapy using intravesical Bacillus Calmette-Guerin (BCG) has been reported although there are concerns regarding recurrence and progression with this approach. Due to the ongoing BCG shortage, we have utilized sequential intravesical gemcitabine and docetaxel (Gem/Doce) as primary therapy for NMIBC, including some cases with limited MP urothelial carcinoma (MPUC). To compare oncologic outcomes of patients with non-muscle invasive MPUC and conventional UC treated with Gem/Doce. MethodsA secondary analysis of 138 patients with high-risk NMIBC treated with intravesical Gem/Doce from January 2011 to December 2021 was performed. Oncologic outcomes were compared in patients with or without MPUC using the Kaplan-Meier method. ResultsMedian follow-up (f/u) for all patients was 23 months (IQR 13–34). There were 129 patients with pure UC and 9 with MPUC. In those with MPUC, all were high-grade (HG), 8/9 were stage T1, 7/9 had a focal MP component (extent < 10%), 3/9 had concomitant CIS, and 2/9 had lymphovascular invasion. All MPUC tumors were re-resected, and 4 had T0, 3 had T1 HG, 1 had Ta HG, 1 had carcinoma in situ (CIS); none had residual MP or LVI tumors before Gem/Doce treatment. The 24-month high-grade recurrence-free survival was 89% and 80% in patients with MPUC and pure UC, respectively. Survival outcomes did not significantly differ between patients with and without MPUC. Four patients with MPUC experienced recurrent NMIBC after Gem/Doce, and all were treated successfully with rescue sequential intravesical valrubicin and docetaxel (Val/Doce). Pathology of these four recurrent patients revealed more aggressive histologic features in the original tumor including: multifocal tumor (3/4), T1 HG disease (4/4), concomitant CIS (2/4), and moderate MP variant extent (30%) (1/4). No patient with MPUC underwent cystectomy, experienced progression, or died at last follow-up (median f/u of 43 months). ConclusionsGem/Doce with Val/Doce rescue appears to have activity against carefully selected non-muscle invasive MPUC with favorable histology. Larger prospective trials are needed to validate these results.

Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial

The KEYNOTE-057 trial evaluated activity and safety of pembrolizumab in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer who were ineligible for or declined radical cystectomy. In cohort A (patients with carcinoma in situ, with or without papillary tumours) of the KEYNOTE-057 study, pembrolizumab monotherapy led to a complete response rate of 41% at 3 months, and 46% of responders maintained a response lasting at least 12 months. Here, we evaluate pembrolizumab monotherapy in cohort B of patients with papillary tumours without carcinoma in situ. KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. Between April 12, 2016, and June 17, 2021, 132 patients (104 [79%] men and 28 [21%] women) who had received a median of ten (IQR 9-15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6-27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45·4 months (IQR 36·4-59·3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43·5% (95% CI 34·9-51·9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three [2%] patients) and diarrhoea (in two [2%]). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients [2%]) was most common. No treatment-related deaths occurred. Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial. Merck Sharp & Dohme.

EarlyTect BCD, a Streamlined PENK Methylation Test in Urine DNA, Effectively Detects Bladder Cancer in Patients with Hematuria

The current noninvasive diagnostic approaches for detecting bladder cancer (BC) often exhibit limited clinical performance, especially for the initial diagnosis. This study aims to evaluate the validity of a streamlined urine-based PENK methylation test called EarlyTect BCD in detecting BC in patients with hematuria scheduled for cystoscopy in Korean and American populations. The test seamlessly integrates two steps, linear target enrichment and quantitative methylation-specific PCR within a single closed tube. The detection limitation of the test was approximately two genome copies of methylated PENK per milliliter of urine. In the retrospective training set (n=105), an optimal cutoff value was determined to distinguish BC from non-BC, resulting in a sensitivity of 87.3% and a specificity of 95.2%. In the prospective validation set (n=210, 122 Korean and 88 American patients), the overall sensitivity for detecting all stages of BC was 81.0%, with a specificity of 91.5% and an area under the curve value of 0.889. There was no significant difference between the two groups. The test achieved a sensitivity of 100% in detecting high-grade Ta and higher stages of BC. The negative predictive value of the test was 97.7%, and the positive predictive value was 51.5%. The findings of this study demonstrate that EarlyTect BCD is a highly effective noninvasive diagnostic tool for identifying BC among patients with hematuria.

Pembrolizumab with favezelimab or vibostolimab for patients with bacillus Calmette-Guérin (BCG)–unresponsive high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): Phase 2 KEYNOTE-057 cohort C.

TPS719 Background: In cohort A of the phase 2 KEYNOTE-057 study (NCT02625961), the PD-1 inhibitor pembrolizumab demonstrated antitumor activity (3-month complete response rate, 41%) in patients with BCG-unresponsive HR NMIBC with carcinoma in situ (CIS) ± papillary tumors who are ineligible for or declined radical cystectomy (RC). However, treatment combinations that improve outcomes and durability of response with pembrolizumab monotherapy are needed. Coinhibitory receptors LAG-3 and TIGIT contribute to immune tolerance in the tumor microenvironment, and co-blockade of PD-1 with LAG-3 or TIGIT has demonstrated antitumor activity in clinical studies. In cohort C of KEYNOTE-057, efficacy and safety of coformulations of pembrolizumab and the LAG-3 inhibitor favezelimab or the TIGIT inhibitor vibostolimab are being evaluated in patients with BCG-unresponsive HR NMIBC with CIS ± papillary tumors. Methods: Key eligibility criteria include adults with histologically confirmed HR NMIBC (CIS ± high-grade Ta or T1 at baseline) that is BCG-unresponsive (persistent or recurrent CIS ± Ta/T1 ≤12 month of completing adequate BCG therapy) who are ineligible for or declined RC and have an ECOG PS of 0-2. Enrollment is planned for 60 patients. Patients will be randomly assigned 1:1 to receive the coformulation of pembrolizumab 200 mg and vibostolimab 200 mg or the coformulation of pembrolizumab 200 mg and favezelimab 800 mg intravenously every 3 weeks for ≤35 cycles or until central pathology–confirmed ≥T1 at any time point, persistent or recurrent CIS or high-grade Ta at 24-week efficacy review or thereafter, unacceptable toxicity, patient or physician decision to withdraw, or administrative reasons to discontinue. Tumor assessment will be performed every 12 weeks for 2 years and every 24 weeks thereafter for up to 5 years. Primary end point is 12-month complete response rate of HR NMIBC by cystoscopy, cytology, biopsy, and radiologic imaging by central pathology and radiology review. Secondary end points include duration of response of HR NMIBC; overall complete response rate and complete response rates at 3 and 6 months; progression-free survival (PFS) to worsening of grade, stage, or death; PFS to muscle-invasive or metastatic disease or death; and overall survival. Efficacy will be evaluated in patients who receive ≥1 dose of treatment and have a baseline evaluation consisting of pre-enrollment cystoscopy, TURBT/biopsy, urine cytology, and baseline CTU imaging. Safety and tolerability will be evaluated in patients who receive ≥1 dose of treatment. Enrollment is ongoing in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT02625961 .

A phase 1 study of IO102-IO103 vaccine plus pembrolizumab in patients with BCG-intolerant or unresponsive non-muscle invasive bladder cancer (NMIBC).

TPS716 Background: Pembrolizumab, an anti-PD1 antibody, is a treatment option for high-risk BCG-unresponsive NMIBC, but has a modest complete response (CR) rate of 41% at 3 months, and a median duration of CR of 16.2 months. IO102-IO103 is a novel immune-modulating cancer vaccine that stimulates activation of T cells targeting indoleamine-2,3-dioxygenase 1 (IDO1) and PDL1-positive cells, resulting in potentially increased susceptibility to anti-PD-1 blockade. Combination IO102-IO103 with nivolumab showed encouraging clinical activity and tolerability in previously anti-PD-1 naïve metastatic melanoma patients (NCT03047928). The existing data for synergistic effects of IO102-IO103 in combination with anti-PD1 therapy and the known expression of IDO in urothelial carcinoma lend rationale to this phase I trial designed to assess the feasibility, safety, and toxicity of IO102-IO103 plus pembrolizumab in patients with BCG-intolerant or unresponsive NMIBC. Methods: This open-label, single arm, phase 1 study enrolls patients with BCG-unresponsive or intolerant high-risk NMIBC who are ineligible for or have declined cystectomy and have adequate ECOG performance status (0-2), hematologic function, and end organ function. High-risk NMIBC is defined as T1, high-grade Ta, or CIS/Tis, with predominantly urothelial cell histology. Exclusion criteria include known active autoimmune disorders requiring immunosuppressive therapy or prior checkpoint inhibitor therapy. Eligible patients will be treated with pembrolizumab 200 mg IV on Day (D) 1, and IO102-IO103 85 mcg SQ on D1 and 8 of a 21-day cycle for the first two cycles, after which IO102-IO103 dosing will be D1 only, with treatment for up to 2 years. The primary endpoints of feasibility, safety, and toxicity will be evaluated by CTCAE v5.0 criteria and will be met if ≥10 patients out of 12 are able to complete the first cycle without experiencing pre-specified treatment-limiting toxicities. Key secondary endpoints include CR rate at 3 months, median duration of response, and cystectomy-free survival at 18 months. Biopsy specimens and serial urine and blood samples will be collected to evaluate potential biomarkers of response. Clinical trial information: NCT05843448 .

Phase 3 KEYNOTE-676 cohort A: Bacillus Calmette-Guérin (BCG) with or without pembrolizumab for high-risk (HR) non–muscle-invasive bladder cancer (NMIBC) that persists/recurs after BCG induction.

TPS722 Background: Intravesical instillation of BCG is a standard-of-care treatment for patients with HR NMIBC, but up to 50% of patients later experience disease recurrence or progression to muscle-invasive bladder cancer (MIBC) despite BCG treatment. In the phase 2 KEYNOTE-057 study (NCT02625961), pembrolizumab monotherapy was shown to have antitumor activity in patients with HR BCG–unresponsive NMIBC who had carcinoma in situ (CIS) with or without papillary tumors and in patients with only papillary tumors. In cohort A of the randomized, phase 3 KEYNOTE-676 trial (NCT03711032), pembrolizumab plus BCG versus BCG alone is being evaluated in patients with persistent/recurrent HR NMIBC after first BCG induction. Methods: Key eligibility criteria include adults with histologically confirmed HR NMIBC (T1, high-grade Ta, and/or CIS) that is persistent/recurrent following 1 adequate course of BCG induction therapy, have no concurrent extravesical disease or history of extravesical disease that recurred within 2 years, have an ECOG PS score of 0 to 2, and have undergone cystoscopy/TURBT ≤12 weeks before randomization. Approximately 430 patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks plus BCG or BCG alone. BCG (50 mg) will be administered by intravesical instillation as induction therapy once weekly for 6 weeks and then as maintenance therapy once weekly for 3 weeks at weeks 13 and 25, then every 24 weeks (Q24W) thereafter. Treatment will continue for approximately 2 years (pembrolizumab) or 3 years (BCG), or until confirmed persistent/recurrent HR NMIBC or disease progression to MIBC or metastatic bladder cancer, unacceptable toxicity, or withdrawal. Randomization to treatment will be stratified by PD-L1 combined positive score (≥10 or ˂10), histology (CIS or non-CIS), and NMIBC disease history (persistence/recurrence 0 to ≤6 months or recurrence ˃6 to ≤12 months or recurrence ˃12 to ≤24 months). Response will be assessed by local cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1 to 2 and Q24W for years 3 to 5. Computed tomography urography will occur every 72 weeks through year 5, then every 104 weeks thereafter. The primary end point is complete response rate in patients with CIS. Secondary end points are duration of response in patients with CIS, event-free survival, recurrence-free survival, time to cystectomy, overall survival, disease-specific survival, safety and tolerability, and patient-reported outcomes. Enrollment incohort A of KEYNOTE-676 is ongoing in Asia, Australia, Europe, and North America. Clinical trial information: NCT03711032 .

Reasons for refusal of or ineligibility for radical cystectomy (RC) in patients (Pts) with bacillus Calmette-Guérin (BCG)–unresponsive high-risk non–muscle-invasive bladder cancer (HR NMIBC) from the SunRISe-1 study.

701 Background: RC is the recommended treatment (tx) option for pts with BCG-unresponsive HR NMIBC. However, RC is associated with significant risk of morbidity, mortality, and impact on quality of life (QoL); some patients may refuse/be ineligible for RC. In a systemic review of 160 real-world studies, &lt;20% of pts with HR NMIBC recurrent after BCG underwent RC (PMID 35046678). For RC-ineligible pts, bladder-sparing tx is recommended. TAR-200, a novel intravesical drug delivery system that provides sustained release of gemcitabine within the bladder, is under investigation in pts with BCG-unresponsive HR NMIBC who are ineligible for/refuse RC in the ongoing ph 2b SunRISe-1 (SR-1) study (NCT04640623). Preliminary results showed a promising complete response (CR) rate of 73% and durable responses in pts with BCG-unresponsive HR NMIBC treated with TAR-200 (Daneshmand et al. AUA 2023). We report reasons for refusal/ineligibility for RC in pts enrolled in the TAR-200 monotherapy cohort of SR-1. Methods: SR-1 is evaluating the efficacy and safety of TAR-200 + cetrelimab (CET; anti–PD-1) (Cohort 1 [C1]), TAR-200 alone (C2), or CET alone (C3). Pts ≥18 y with histologically confirmed carcinoma in situ (CIS) ± papillary disease (T1, high-grade Ta) who completed adequate BCG and recurred ≤12 mo since last BCG dose with ECOG performance status (PS) of 0-2 are randomized to C1, C2, or C3. As of Amendment 4, pts with papillary disease only will be enrolled in C4 with TAR-200 alone. The primary end point is overall CR rate at any time. Refusal/ineligibility for RC was documented in the electronic case report form. Results: As of Aug 24, 2023, 54 pts were treated in C2. Median age was 71 y (range 40-85). Pts had a median of 12 (range 7-42) prior BCG doses with a median of 3.0 mo (range 0.2-22.0) from last BCG dose to recurrence. Most pts (96%) had ECOG PS 0; 33% had CIS with papillary disease. 50%, 48%, and 19% of pts had a medical history of Gr ≥2 metabolic, vascular, and cardiac conditions, respectively, and 9% were current nicotine users. Overall, 51 (94%) pts refused RC; 3 (6%) were ineligible (Table). The most common reason for refusal was a preference for bladder preservation (52%), followed by concern about QoL (37%). Pts were ineligible for RC due to medical/surgical comorbidities (4%) and age (2%). Conclusions: Most pts enrolled in C2 of SR-1 refused RC, with preference for bladder preservation and QoL concerns being the most common reason for refusal. This highlights the need for bladder-sparing tx options for pts with HR NMIBC recurrent after BCG. Clinical trial information: NCT04640623 . [Table: see text]

The need for re-staging transurethral resection of bladder tumour (ReTURBT) in Ta high grade and T1 tumours: Questioning the norms—Inferences from a national institute.

79 Background: The incidence of urinary bladder carcinoma is increasing at an alarming rate. Non-Muscle Invasive Bladder Cancer (NMIBC) accounts for seventy percent of these patients. Current guidelines recommend a Restage Transurethral Resection of Bladder Tumour (ReTURBT) for Ta high-grade and all T1 non-muscle invasive tumours, to increase the accuracy of staging. The question of whether a second surgery is always necessary remains unanswered. Here, the patient's concern about the completeness of the procedure, perioperative morbidity, and the financial burden involved in a major surgery cannot be ignored. Moreover, it also puts a strain on the already overburdened healthcare systems in developing countries like India. Trying to answer this question of whether it is oncologically sound to omit a second resection, our study evaluated the outcomes of patients undergoing restage TURBT with regards to the rate of upstaging, upgrading and residual tumours in these patients. Methods: The study was a retrospective analysis of a prospectively maintained database including NMIBC patients from September 2019 to February 2023. A total of 112 patients underwent restage TURBT. Their demographic details, imaging, cystoscopy findings, and histopathological data were recorded. The primary objective was to analyse the rate of upstaging, while the secondary objectives were to look at the residual tumour and upgrading rates in these patients. Results: Out of 112 patients (T1- 71 &amp; Ta high grade- 41), 24 patients (21.42%) had residual tumours at restage (T1- 20 &amp; Ta high grade- 4) while 21 (18.75%) patients (T1- 19 &amp; Ta high grade- 02) were upstaged to T1 or T2. Grade progression was seen in 15.41 % T1 patients, while none of the Ta high grade patients had a change in grade. Deep muscle in the initial resection was present in 87.5 % of the specimens. Conclusions: Our retrospective analysis points towards skipping a restage TURBT in select Ta patients in whom a well-performed and adequate initial TURBT was done. Further prospective studies with large patient cohorts are needed to confirm and reinforce these proposed facts.

Evaluation of Sensitive Urine DNA-Based PENK Methylation Test for Detecting Bladder Cancer in Patients with Hematuria

Hematuria is a prevalent symptom associated with bladder cancer (BC). However, the invasiveness and cost of cystoscopy, the current gold standard for BC diagnosis in patients with hematuria, necessitate the development of a sensitive and accurate noninvasive test. This study introduces and validates a highly sensitive urine-based DNA methylation test. The test improves sensitivity in detecting PENK methylation in urine DNA using linear target enrichment followed by quantitative methylation-specific PCR. In a case-control study comprising 175 patients with BC and 143 patients without BC with hematuria, the test's optimal cutoff value was determined by distinguishing between two groups, achieved an overall sensitivity of 86.9% and a specificity of 91.6%, with an area under the curve of 0.892. A prospective validation clinical study involving 366 patients with hematuria scheduled for cystoscopy assessed the test's performance. The test demonstrated an overall sensitivity of 84.2% in detecting 38 cases of BC, a specificity of 95.7%, and an area under the curve of 0.900. Notably, the sensitivity for detecting Ta high grade and higher stages of BC reached 92.3%. The test's negative predictive value was 98.2%, and the positive predictive value was 68.7%. These findings highlight the potential of the PENK methylation in urine DNA using linear target enrichment followed by quantitative methylation-specific PCR test in urine as a promising molecular diagnostic tool for detecting primary BC in patients with hematuria, which may reduce the need for cystoscopy.

An in-progress phase 2 window of opportunity (WOO) trial of targeted therapy with erdafitinib for patients with recurrent FGFR3-altered non–muscle-invasive bladder cancer (NMIBC).

TPS4614 Background: Alterations to FGFR3 are the most common somatic mutations in non-muscle invasive bladder cancer (NMIBC), present in 40-60% of high-grade Ta and &gt; 80% of recurrent low grade Ta tumors. FGFR3 mutations are also known to be associated with a “cold” tumor microenvironment (TME) that may mediate BCG resistance. Erdafitinib, a targeted inhibitor of FGFR 1-4, is the first FDA approved targeted therapy for locally advanced/metastatic bladder cancer. As FGFR3 mutations are present 3-5x more commonly in NMIBC than metastatic disease, erdafitinib is a logical therapeutic candidate for FGFR3-altered NMIBC. Through this ongoing phase II trial, we seek to determine the safety and efficacy of erdafitinib for the treatment of intermediate and high risk FGFR3-altered NMIBC after prior intravesical therapy. Methods: To address the need for expanded targeted therapeutics for NMIBC,, we launched an investigator-initiated phase II window of opportunity (WOO) trial of erdafitinib (NCT04917809, PI Pietzak). We are currently enrolling patients with intermediate or high risk NMIBC with history of ≥1 or more induction courses of BCG and/or intravesical chemotherapy who present with a clinically staged Ta papillary recurrence on office cystoscopy. Patients are also required to have an oncogenic FGFR3 mutation or fusion, as confirmed by OncoKB on MSK-IMPACT, to be included in the trial. Trial patients are treated with 6 mg oral erdafitinib daily for 28 days during the “window of opportunity” time period between office cystoscopy and transurethral resection of the recurrent bladder tumor (TURBT). The primary outcome is the rate of objective response, defined as complete (no visible tumor) or partial ( &gt; 50% reduction of measured diameter by Response Evaluation Criteria for Tumors of the Bladder [RECIT-Bladder]) as compared to cystoscopy at TURBT. We are employing an optimal Simon two-stage binomial design, assuming an objective response of &gt; 15% would and &lt; 2% would not be worthy of further study. We plan to enroll 16 patients in the first stage and 9 in the second (87% power). Secondary outcomes include safety (CTAE 5.0), patient reported outcomes, and recurrence-free survival. Correlative studies will be conducted with urine, blood, and tumor tissue samples. Urine and blood are collected before (day 1), during (day 14) and after treatment (day 28) and will undergo immune and molecular studies to understand shifts in the microenvironment in the setting of response and resistance. This trial is being conducted in parallel with a co-clinical trial of patient derived organoid/xenograft models (MSK 19-015, PI Pietzak) to further refine the understanding of FGFR3 mutational resistance to standard treatment and the effects of targeted immunotherapy on tumor clinicogenomics. Clinical trial information: NCT04917809 .

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

LBA03-08 PEMBROLIZUMAB (PEMBRO) FOR PATIENTS (PTS) WITH HIGH-RISK NON-MUSCLE-INVASIVE BLADDER CANCER (HR NMIBC) UNRESPONSIVE TO BACILLUS CALMETTE-GUERIN (BCG): EFFICACY AND EVALUATION OF SUBSEQUENT CYSTECTOMY FROM COHORT B OF THE PHASE 2 KEYNOTE-057 STUDY

LBA03-08 PEMBROLIZUMAB (PEMBRO) FOR PATIENTS (PTS) WITH HIGH-RISK NON-MUSCLE-INVASIVE BLADDER CANCER (HR NMIBC) UNRESPONSIVE TO BACILLUS CALMETTE-GUERIN (BCG): EFFICACY AND EVALUATION OF SUBSEQUENT CYSTECTOMY FROM COHORT B OF THE PHASE 2 KEYNOTE-057 STUDY

LBA02-03 FIRST RESULTS FROM SunRISE-1 IN PATIENTS WITH BCG UNRESPONSIVE HIGH-RISK NON–MUSCLE-INVASIVE BLADDER CANCER RECEIVING TAR-200 IN COMBINATION WITH CETRELIMAB, TAR-200, OR CETRELIMAB ALONE

LBA02-03 FIRST RESULTS FROM SunRISE-1 IN PATIENTS WITH BCG UNRESPONSIVE HIGH-RISK NON–MUSCLE-INVASIVE BLADDER CANCER RECEIVING TAR-200 IN COMBINATION WITH CETRELIMAB, TAR-200, OR CETRELIMAB ALONE

Preliminary results from a phase II study of tislelizumab combined with radiotherapy as bladder-preserving treatment for patients with high-risk non-muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette-Guerin (BCG).

510 Background: Radical cystectomy (RC) was recommended to patients (pts) with HR NMIBC BCG-unresponsive papillary tumors. Clinical unmet need was to explore non-surgical treatment options for pts who were ineligible for or refused RC. Our study aimed to evaluate the efficacy and safety of tislelizumab combined with radiotherapy as bladder-preserving treatment for pts with HR NMIBC unresponsive to BCG. Methods: This open-label, single arm phase II study enrolled pts with HR NMIBC BCG-unresponsive papillary tumors (high-grade Ta or T1 tumors without carcinoma in situ). The papillary tumors should be removed all visible lesions by transurethral resection of bladder tumor (TURBT). Within 2 weeks after TURBT, eligible pts received tislelizumab 200 mg in day 1 (D1), every 21 days for eight cycles and a total radiotherapy dose of 60-66 GY in 30-33 fractions over seven weeks. The primary end point was disease-free survival (DFS) rate at 12 months (defined as no reappearance of high grade or T1 tumors or clinical stage development after the therapy). Secondary end points were bladder-preservation rate, OS and safety. Our study anticipated a DFS rate at 12 months was 45% and the study would enroll 32 pts to meet the primary endpoint. Results: By Sep. 2022, 14 eligible pts were enrolled. Ten pts have completed therapy and were analyzed (male 90.0%; median age 58 years (31-79); pure TCC 100%; median tumor size 1.0 cm (0.5-2.0); 40% multiple papillary tumours; median eGFR, 91.1 mL/(min•1.73m2) (46.1-115.5); high-grade Ta 40.0%, T1 60.0%; median of 11 previous BCG instillations (9-19)). Median follow-up was 20.3 months (9.9-28.1), the median number of tislelizumab cycles was 8 (2-8) and radiotherapy doses was 60 GY (60-66) in 30 fractions. The DFS rate at 12 month was 80.0% (95%CI, 67.4%-92.6%), at 24 month was 60.0% (95%CI, 40.3%-79.7%). Two pts showed reappearance of high-grade Ta and received TURBT, one patient showed stage development from T1N0M0 to M1 disease and received systemic treatment. The bladder-preservation rate at 24 months was 100% (95%CI, 100%-100%). The OS rate at 24 months was 100% (95%CI, 100%-100%). Treatment related adverse events (TRAEs) of any grade were rash (40.0%), neutropenia (10.0%), hyperthyroidism (10.0%), AST/ALT increased (10.0%) and hyperglycaemia (10.0%). 5 pts experienced immune related AEs, including rash (n=4, G1-2), hyperthyroidism (n=1, G2), hyperglycaemia (n=1, G3) and AST/ALT increased (n=1, G3). Conclusions: Our preliminary results supported the use of tislelizumab combined with radiotherapy as a promising bladder-preserving therapy for pts with BCG-unresponsive HR NMIBC who were ineligible for or refused RC. Clinical trial information: ChiCTR2000035275 .

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 &gt;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]

Can repeat TURBT in patients presenting with High Grade Ta Urothelial Carcinoma be more nuanced?

Can repeat TURBT in patients presenting with High Grade Ta Urothelial Carcinoma be more nuanced?