Efficacy and Safety of Keyhole Limpet Hemocyanin in Bacillus Calmette-Guérin Unresponsive Non-muscle Invasive Bladder Cancer.

595 Background: Intravesical Bacillus Calmette-Guerin (BCG) induction + BCG maintenance after transurethral resection is the current standard of care for patients (pts) with high-risk non-muscle invasive bladder cancer (NMIBC). Recurrence rate at 2 years and 5 years are around 30-40% and 70-80% respectively. Atezolizumab is a IgG1 monoclonal antibody targeting PD-L1 and is associated with long-term durable remissions in pts with metastatic urothelial cancer (MS. van der Heijden . Eur Urol 2021) and for pts with unresponsive NMIBC (PC. Black . Eur Urol 2023) with excellent results. Atezolizumab in combination with standard BCG could provide synergistic benefit for pts with NMIBC. BladderGATE (NCT04134000) is a phase Ib-II study which evaluates the safety and efficacy of upfront atezolizumab + intravesical BCG in pts with high-risk NMIBC. Methods: Pt had confirmed histopathology of high-risk NMIBC, BCG naïve or stopped >2 years ago, WHO PS 0-2 and adequate hematologic and organ function. Dose-escalation design to identify DLT and MTD (9 pts) and to evaluate safety and efficacy in an expansion cohort (30 pts) were programed. Pt received six weekly induction instillations, and maintenance instillations at 3, 6 and 12 months + intravenously atezolizumab 1200 mg every 3 weeks, up to 1 year. Urine/blood and tissue samples were collected for translational and biomarker correlative study. Primary objective is disease free survival. Secondary objectives include safety profile and quality of life. Results: Finally 36 pt were included, median age 70 years, 86% men, 61% of pt were former smokers, 22% smokers and 17% had never smoked, and tumor size was ≥3 cm in 44% of pt. With a 22 months median follow-up, 56% of pt had completed BCG treatment and 89% had received adequate BCG treatment (5 induction plus at least 2 maintenance instillations). Thirteen pts discontinued atezolizumab due to immune-related AEs (7 pts) (g2 dermatitis, g3 hepatitis, encephalitis, pneumonitis, myocarditis, adrenal insufficiency and psoriasis), due to early-relapse disease (3 pts) and progressive-disease (3 pts). All irAEs were solved and no toxic death were reported. Of the 36 pts analyzed, 6 pts showed local recurrence (17%), 5 pts with high-risk NMIBC (14%) and 1 pt with low-risk NMIBC, 1 pt with UTUC, and 3 pts with local muscle invasive bladder cancer progressive-disease (8 %). Preliminary 2-year disease free survival is 72.8% (95% CI: 56.1% - 89.5%). Conclusions: The combination strategy of atezolizumab + intravesical BCG upfront in high-risk NMIBC pts appears feasible and safe. A 14% of 2-years local recurrence-rate and 8% of local progressive-disease are promising results, pending to randomized Ph3 ALBAN study data (GETUG). Supported by Roche-Spain. Clinical trial information: NCT03425201 .

TPS4591 Background: Intravesical instillation of BCG is standard of care for patients (pts) with HR NMIBC. However, many pts have persistent/recurrent HR NMIBC after BCG induction and are at increased risk for progression to muscle-invasive disease. Interim data from the phase 2 KEYNOTE-057 study has shown that the PD-1 inhibitor pembro had promising efficacy in HR NMIBC as monotherapy. KEYNOTE-676 (NCT03711032) is a randomized, comparator-controlled, phase 3 trial to evaluate efficacy and safety of pembro plus BCG in pts with persistent/recurrent HR NMIBC after BCG induction therapy. Methods: Pts are randomly assigned 1:1 to continue BCG therapy alone or receive BCG plus pembro 200 mg every 3 weeks. Treatment is stratified by carcinoma in situ (CIS) histology (presence/absence), PD-L1 combined positive score (≥10/˂10), and timing of NMIBC persistence/recurrence (0 to ≤6, ˃6 to ≤12, or ˃12 to ≤24 mo). Pts are eligible if they are ≥18 years of age with histologically confirmed persistent/recurrent HR NMIBC of the bladder after adequate BCG induction therapy, have undergone cystoscopy/transurethral resection of bladder tumor within 12 weeks before randomization, have no concurrent extravesical disease, and have an ECOG PS score of 0-2. Responses are assessed by cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1-2 and every 24 weeks for years 3-5 and by computed tomography urography every 18 months through year 5. Treatment will continue with pembro for up to 2 years and BCG for 3 years or until confirmed HR NMIBC persistence, recurrence, or disease progression, unacceptable toxicity, or pt/physician decision to withdraw. Primary end point is complete response rate in pts with CIS. Secondary end points are event-free survival (EFS), recurrence-free survival, overall survival, disease-specific survival, time to cystectomy, 12-month EFS rate in all pts, duration of response (DOR), 12-month DOR rate in pts with CR and safety and tolerability. Recruitment began in November 2018 and will continue until ~550 pts are enrolled. Clinical trial information: NCT03711032.

Hyperthermic Intravesical Chemotherapy for BCG Unresponsive Non-Muscle Invasive Bladder Cancer Patients

573 Background: Intravesical bacillus Calmette-Guérin (BCG) is the first-line treatment for high-risk non-muscle invasive bladder cancer (NMIBC). Unfortunately, disease recurrence/progression is common and associated with increased risk of death from bladder cancer. While radical cystectomy remains the preferred treatment for BCG unresponsive NMIBC, many patients are either unwilling or unfit to undergo surgery. Previous retrospective studies have demonstrated the efficacy of intravesical gemcitabine and docetaxel (Gem/Doce) for treating NMIBC after BCG failure. However, the long-term outcomes of this cohort are unknown. We report 5-year survival outcomes of patients treated with intravesical Gem/Doce after BCG failure. Methods: We retrospectively identified patients at our institution who were treated with Gem/Doce for high-risk NMIBC after BCG failure between 2009 and 2017. Patients received six weekly intravesical Gem/Doce instillations. Initial responders received monthly maintenance instillations for 2 years. Surveillance was performed according to American Urological Association guidelines. Survival time was measured from start of Gem/Doce induction. Outcomes included high-grade recurrence-free survival (HG-RFS), progression-free survival (PFS), cystectomy-free survival (CFS), cancer-specific survival (CSS) and overall survival (OS). Recurrence was defined as pathologically confirmed tumor relapse in the bladder or prostatic urethra. Progression was defined as recurrence of disease with stage T2 or greater, cystectomy or death due to bladder cancer. Survival probabilities were calculated with the Kaplan-Meier method. Results: A total of 97 patients with a median age of 73 years were treated with Gem/Doce after BCG failure. Median follow-up was 49 months. BCG failure was further stratified as BCG unresponsive (35%), BCG relapsing (38%), BCG intolerant (11%) or unspecified (16%). 71% and 21% of patients had carcinoma in-situ and high-grade T1 disease, respectively. Complete response at initial surveillance was 74% and median duration of response was 26 months. Overall HG-RFS at 1, 2 and 5 years was 60%, 51% and 31%, respectively. HG-RFS was similar among BCG unresponsive patients and the overall cohort (see table). During follow-up, 18 patients (19%) underwent radical cystectomy and 28 patients (29%) experienced disease progression. PFS, CFS, CSS and OS at 5 years was 68%, 75%, 91% and 64%, respectively. Conclusions: Intravesical Gem/Doce for high-risk NMIBC after BCG failure offers long-term efficacy and substantial durability of response with a high likelihood of bladder preservation at five years after induction. Future prospective trials assessing Gem/Doce are warranted.[Table: see text]

4606 Background: BCG is the standard therapy after transurethral resection of bladder tumor for high-risk NMIBC. IL-15 agonists can enhance the immune response induced by BCG via stimulating the proliferation and activation of natural killer cells and CD8+ cytotoxic T cells, without inducing regulatory T cells. SHR-1501 is an IL-15 agonist fusion protein, composed of a humanized antibody Fc region fused with IL-15 and IL-15Rα sushi domain. In this phase 1/2 study, we assessed the safety, tolerability, and efficacy of SHR-1501 in patients (pts) with high-risk NMIBC. Methods: The study comprised dose-escalation phase 1a and 1b parts of SHR-1501 alone or in combination with BCG in pts with high-risk NMIBC, followed by a phase 2 part of SHR-1501 plus BCG in multiple cohorts, including pts with BCG-naive NMIBC (cohort A), BCG-unresponsive NMIBC carcinoma in situ (CIS; cohort B), and BCG-unresponsive high-grade Ta/T1 NMIBC without CIS (cohort C). All pts received intravesical study treatment weekly for 6 weeks during induction period. During maintenance period, instillations occurred weekly for the first 3 weeks at 3, 6, 12, 18, and 24 months after the initial induction instillation. Primary endpoints were dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended phase 2 dose in phase 1a and 1b parts; and was complete response (CR) rate for cohort B and 12-mo disease-free survival (DFS) rate for cohorts A and C in phase 2 part. Results: As of Sep 7, 2024, 84 pts were enrolled (n = 8 in phase 1a; n = 6 in phase 1b; n = 29, 17, and 24 in cohorts A, B, and C in phase 2). In phase 1a part of SHR-1501 alone (200, 400, and 600 μg) and phase 1b part of SHR-1501 (600 μg) plus BCG (120 mg), no DLTs were observed, and MTD was not reached. Thus, 600 μg of SHR-1501 plus 120 mg of BCG was used in phase 2 part. Treatment-related adverse events (TRAEs) occurred in 4 (50.0%) of 8 pts with SHR-1501 and 53 (69.7%) of 76 pts with SHR-1501 + BCG. Grade 3 TRAEs were reported in 1 (12.5%) pt with SHR-1501 (urinary tract infection) and 7 (9.2%) pts with SHR-1501 + BCG (urinary tract infection and hypertension occurred in > 1 pt). No grade 4 or 5 TRAEs were reported. No serious TRAEs occurred. Of the efficacy evaluable pts in cohort B, the CR rate at 3 or 6 months was 90.9% (10/11). In cohorts A and C, the 12-month DFS rate was not reached. The 9-month DFS rate was 94.4% (95% CI, 66.6-99.2) in cohort A and 53.9% (95% CI, 15.5-81.4) in cohort C. Conclusions: SHR-1501 alone or in combination with BCG was well-tolerable and demonstrated a favorable efficacy in BCG-naive and BCG-unresponsive high-risk NMIBC pts, supporting further investigations. Clinical trial information: NCT05410730 .

IntroductionRadical cystectomy remains the standard treatment for intravesical Bacille Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) because potential bladder-preserving therapies are not well established. Combination of radiotherapy with programmed...

Over the last decade, the world has experienced health-threatening supply shortages of Bacillus Calmette-Guérin (BCG) immunotherapy for nonmuscle-invasive bladder cancer (NMIBC). We summarize the current literature to assist in treatment decisions in light of suboptimal supply. Currently available data do not support a superiority of one BCG strain over the other. Intravesical chemotherapy seems to provide similar results in term of disease progression but not recurrence in intermediate-risk patients. One trial has shown that a 3-year maintenance course of BCG in high-risk NMIBC has no advantage in term of progression or overall survival in comparison with 1-year maintenance. Synergo radiofrequency-induced hyperthermia is a reliable alternative in intermediate or high-risk NMIBC with at least similar recurrence rates compared with BCG. Patients with intermediate-risk NMIBC can be offered multiple instillations of intravesical chemotherapy for up to 12 months. In high-risk patients and in case of BCG shortage, BCG instillations can be terminated when the patient has completed 1 year of maintenance. Mitomycin C is an alternative in lowest risk high-risk (G3Ta) NMIBC, whereas patients with pT1/carcinoma in situ can be offered Synergo with mitomycin C when radical cystectomy is not feasible. Immediate radical cystectomy should always be considered in highest risk NMIBC after weighing up benefit to risk.

507 Background: Combination intravesical Gemcitabine and Docetaxel (GEMDOCE) has demonstrated benefit for bacillus Calmette-Guérin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) in retrospective series and is now being widely utilized as salvage therapy. BCG therapy is fraught with frequent drug shortages and some patients are unable to tolerate BCG due to side effects. Given ongoing BCG shortages as well as the promising efficacy and tolerability of GEMDOCE as a salvage therapy, our objective was to investigate the safety and efficacy of intravesical GEMDOCE for high-risk (HR) BCG-naïve NMIBC in a prospective manner. Methods: This study is an IRB-approved prospective single-arm open-label phase II trial for patients with BCG-naïve HR NMIBC. Intravesical gemcitabine (1,000 mg)/docetaxel (40 mg) in 100mL normal saline is given weekly for 6 weeks as induction followed by monthly maintenance therapy for 2 years among responders. The primary endpoint was 3-month complete response (CR), defined as a negative bladder biopsy 6 weeks after induction treatment. Secondary endpoints included adverse events (AE) and 12-month CR. Results: To date, the study has fully accrued with 25 patients enrolled from July 2020-August 2022. The pre-trial pathologic stages in our cohort were as follows: HGT1 with CIS (n = 7), HGT1 without CIS (n = 6), HGTa (n = 9), and CIS alone (n = 3) (Table). All 25 patients who completed induction therapy demonstrated CR at 3 months. Eight out of 9 (89%) patients with at least 12 months of follow-up demonstrated continued CR. One patient with HGT1 + CIS on enrollment developed a recurrence at 9 months with HGTa. No enrolled patients have undergone radical cystectomy. Grade 1 AEs were common (19/25 patients, 76%) including hematuria, urinary frequency, urgency, and fatigue. Two patients (8%) experienced a Grade 3 AE including urinary retention and UTI requiring hospitalization and intravenous antibiotics. Conclusions: In this ongoing single-arm phase II trial, GEMDOCE appears to be well-tolerated with promising short-term efficacy for patients with BCG-naïve HR NMIBC. [Table: see text]

473 Background: For patients with intermediate- to high-risk non-muscle invasive bladder cancer (NMIBC), standard of care includes transurethral resection (TURBT) followed by induction and maintenance intravesical immunotherapy with Bacillus Calmette-Guerin (BCG). This study describes characteristics and clinical outcomes of Medicare beneficiaries newly diagnosed with NMIBC who initiated BCG therapy following TURBT. Methods: Retrospective cohort study using Centers for Medicare and Medicaid-sourced Medicare Fee-for-Service medical/pharmacy claims (100% sample). Patient selection criteria: ≥1 bladder cancer diagnosis 2010-2019, no prior radiotherapy, systemic therapy, cystectomy, or metastasis in 6 months post-diagnosis, continuously enrolled in Medicare ≥12 months pre- and post-index (or death). Index date = date of first BCG instillation. A literature-based definition for adequate maintenance BCG defined adequate (≥7 instillations of BCG within 274 days of BCG initiation) and inadequate (remainder) BCG therapy for patient stratification. Events: time to BCG discontinuation, radical cystectomy, systemic therapy, radiation, and metastasis. Provider access to BCG (due to supply shortage), patient tolerability, and NMIBC risk status are not captured in claims data. Results: Of 46,052 BCG-treated patients eligible for analysis, 19,859 (43.1%) received adequate BCG therapy. The two cohorts had similar baseline characteristics (Table) and median duration of follow up (46 months). Median (interquartile range [IQR]) time from NMIBC diagnosis to BCG initiation was 2.8 (8.2) months for adequate, 3.7 (14.4) months for inadequate BCG. Time from BCG initiation to discontinuation, radical cystectomy, systemic therapy, radiation, and metastasis are reported in the table. Conclusions: Between 2010 and 2019, 57% of Medicare patients initiating BCG following diagnosis of NMIBC and TURBT may not have received adequate BCG therapy. Patients with inadequate BCG therapy had numerically shorter time to radical cystectomy, systemic therapy, radiation, and metastasis than those with adequate BCG therapy. Characteristics & Outcomes by Cohort. [Table: see text]

TPS502 Background: Intravesical instillation of BCG is the standard of care for patients with HR NMIBC. However, many patients have persistent/recurrent HR NMIBC after BCG induction and are at a particularly increased risk for progression, representing a significant unmet need. Programmed cell death ligand 1 (PD-L1) expression in the tumor microenvironment may attenuate responses to BCG. KEYNOTE-676 is a randomized, comparator-controlled, phase 3 trial to evaluate the efficacy and safety of the PD-1 inhibitor pembro plus BCG in patients with persistent/recurrent HR NMIBC after BCG therapy. Methods: Adult (≥18 years) patients with histologically confirmed persistent/recurrent HR NMIBC of the bladder after adequate BCG induction therapy are eligible. Patients are required to have undergone cystoscopy/transurethral resection of bladder tumor within 12 weeks prior to randomization, to have no concurrent extravesical disease, and to have ECOG performance status score 0-2, adequate organ function, and tissue for biomarker analysis. Patients will be randomly assigned 1:1 to continue on BCG therapy alone or receive BCG plus pembro 200 mg every 3 weeks. Treatment will be stratified by carcinoma in situ (CIS) histology (presence/absence), PD-L1 combined positive score (≥10/˂10), and timing of NMIBC persistence/recurrence (0 to ≤6, ˃6 to ≤12, or ˃12 to ≤24 mo). Primary end point is complete response rate in participants with CIS. Secondary end points will include event-free survival, patient-reported outcomes, and safety. Responses will be assessed by cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1-2 and every 24 weeks for years 3-5 and by computed tomography urography every 18 months through year 5. Treatment will continue with pembro for up to 2 years and BCG for 3 years or until pathology-confirmed HR NMIBC persistence, recurrence, or disease progression, unacceptable toxicity, or patient/physician decision to withdraw. Recruitment will begin November 2018 and will continue until ~550 patients are enrolled. (NCT03711032). Clinical trial information: NCT03711032.

Systematic review and meta-analysis of radiation therapy for high-risk non-muscle invasive bladder cancer

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 .

PCN233 TREATMENT PATTERNS IN HIGH-RISK, BACILLE CALMETTE-GUÉRIN UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER PATIENTS: A SYSTEMATIC LITERATURE REVIEW

MP71-19 ULTRASENSITIVE URINARY LIQUID BIOPSY ANALYSIS FOR BCG RESPONSE ASSESSMENT IN HIGH-RISK NON-MUSCLE INVASIVE BLADDER CANCER

Bacillus Calmette-Guerin (BCG) therapy is safe and effective in non-muscle invasive bladder cancer (NMIBC) patients with immunomodulating conditions