Intermediate-risk Non-muscle-invasive Bladder Cancer Research Articles

Abstract B024: Development of HM-001 as a therapeutic drug for non-muscle invasive bladder cancer

Abstract HM-001 is a drug containing sodium chlorite as the active ingredient that is being developed as a drug for non-muscle invasive bladder cancer (NMIBC), and is currently undergoing physician-led clinical trials. It has been discovered that sodium chlorite generates radicals in an acidic environment, and phosphatidylserine on the surface of tumor cells acts as a Lewis acid to generate radicals. HM-001, like other anticancer drugs and BCG, is intended to be injected into the bladder, retained, and then excreted. GLP studies using the same administration method has been completed, and no toxic changes have been observed in human trial doses. The efficacy of HM-001 against NMIBC was evaluated using an orthotopic transplantation model of UM-UC-3, a bladder cancer cell line. In the model, cells were transplanted into the bladder of SCID mouse after epithelial removal with trypsin, 600, 800, 1,600, and 3,200 ppm of HM-001 were administered once a week, and the weight of the excised bladder was calculated. After 4 weeks, the tumor weight was calculated and the tumor weight suppression rate in the control group was evaluated. As a result, the medicinal efficacy was confirmed at concentrations of 800ppm or higher. On the other hand, the UM-UC-3 model is a commonly used model, but it mimics CIS (carcinoma in situ) and can only partially mimic NMIBC. That is, other models are needed to evaluate efficacy for low- and high-grade NMIBC other than CIS. Therefore, we established high-grade and low-grade PDX and evaluated the effectiveness of HM-001 against low- and high-grade PDX through ex vivo testing. First, patient-derived tissue was transplanted into SCID mice, allowed to grow, and then removed. After extraction, they were cut into 2 mm3 pieces, exposed to HM-001 at 800, 1600, and 3200 ppm for 2 hours, and then transplanted into SCID mice. As a result of comparing the tumor size after transplantation with the control group, a dose-dependent tumor regression effect was confirmed in high-grade and low-grade PDX. NMIBC is divided into low-, medium-, and high-risk categories, with different treatment methods and drugs used for each. In particular, low-grade forms are restricted to low- and intermediate-risk groups. The results of this study show that HM-001 is effective not only for high-risk (including CIS) NMIBC but also for low- and intermediate-risk (low-grade) NMIBC. Citation Format: Shinji Mima, Monta Sakaki, Noriaki Kiya, Atsunari Kawashima, Norio Nonomura, Chihaya Kakinuma. Development of HM-001 as a therapeutic drug for non-muscle invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B024.

The International Bladder Cancer Group Intermediate-Risk Non-muscle Invasive Bladder Cancer Scoring System Predicts the Need for Intervention for Patients on Active Surveillance

The International Bladder Cancer Group Intermediate-Risk Non-muscle Invasive Bladder Cancer Scoring System Predicts the Need for Intervention for Patients on Active Surveillance

Transurethral En Bloc Resection Versus Standard Resection of Bladder Tumour: A Randomised, Multicentre, Phase 3 Trial

BackgroundConventionally, standard resection (SR) is performed by resecting the bladder tumour in a piecemeal manner. En bloc resection of the bladder tumour (ERBT) has been proposed as an alternative technique in treating non–muscle-invasive bladder cancer (NMIBC). ObjectiveTo investigate whether ERBT could improve the 1-yr recurrence rate of NMIBC, as compared with SR. Design, setting, and participantsA multicentre, randomised, phase 3 trial was conducted in Hong Kong. Adults with bladder tumour(s) of ≤3 cm were enrolled from April 2017 to December 2020, and followed up until 1 yr after surgery. InterventionPatients were randomly assigned to receive either ERBT or SR in a 1:1 ratio. Outcome measurements and statistical analysisThe primary outcome was 1-yr recurrence rate. A modified intention-to-treat analysis on patients with histologically confirmed NMIBC was performed. The main secondary outcomes included detrusor muscle sampling rate, operative time, hospital stay, 30-d complications, any residual or upstaging of disease upon second-look transurethral resection, and 1-yr progression rate. Results and limitationsA total of 350 patients underwent randomisation, and 276 patients were histologically confirmed to have NMIBC. At 1 yr, 31 patients in the ERBT group and 46 in the SR group developed recurrence; the Kaplan-Meier estimate of 1-yr recurrence rates were 29% (95% confidence interval, 18–37) in the ERBT group and 38% (95% confidence interval, 28–46) in the SR group (p = 0.007). Upon a subgroup analysis, patients with 1–3 cm tumour, single tumour, Ta disease, or intermediate-risk NMIBC had a significant benefit from ERBT. None of the patients in the ERBT group and three patients in the SR group developed progression to muscle-invasive bladder cancer; the Kaplan-Meier estimates of 1-yr progression rates were 0% in the ERBT group and 2.6% (95% confidence interval, 0–5.5) in the SR group (p = 0.065). The median operative time was 28 min (interquartile range, 20–45) in the ERBT group and 22 min (interquartile range, 15–30) in the SR group (p < 0.001). All other secondary outcomes were similar in the two groups. ConclusionsIn patients with NMIBC of ≤3 cm, ERBT resulted in a significant reduction in the 1-yr recurrence rate when compared with SR (funded by GRF/ECS, RGC, reference no.: 24116518; ClinicalTrials.gov number, NCT02993211). Patient summaryConventionally, non–muscle-invasive bladder cancer is treated by resecting the bladder tumour in a piecemeal manner. In this study, we found that en bloc resection, that is, removal of the bladder tumour in one piece, could reduce the 1-yr recurrence rate of non–muscle-invasive bladder cancer.

Abstract 3329: Development of HM-001 as a therapeutic drug for non-muscle invasive bladder cancer

Abstract HM-001 is a drug containing sodium chlorite as the active ingredient that is being developed as a drug for non-muscle invasive bladder cancer (NMIBC), and is currently undergoing physician-led clinical trials. It has been discovered that sodium chlorite generates radicals in an acidic environment, and phosphatidylserine on the surface of tumor cells acts as a Lewis acid to generate radicals. HM-001, like other anticancer drugs and BCG, is intended to be injected into the bladder, retained, and then excreted. GLP studies using the same administration method has been completed, and no toxic changes have been observed in human trial doses. The efficacy of HM-001 against NMIBC was evaluated using an orthotopic transplantation model of UM-UC-3, a bladder cancer cell line. In the model, cells were transplanted into the bladder of SCID mouse after epithelial removal with trypsin, 600, 800, 1,600, and 3,200 ppm of HM-001 were administered once a week, and the weight of the excised bladder was calculated. After 4 weeks, the tumor weight was calculated and the tumor weight suppression rate in the control group was evaluated. As a result, the medicinal efficacy was confirmed at concentrations of 800ppm or higher. On the other hand, the UM-UC-3 model is a commonly used model, but it mimics CIS (carcinoma in situ) and can only partially mimic NMIBC. That is, other models are needed to evaluate efficacy for low- and high-grade NMIBC other than CIS. Therefore, we established high-grade and low-grade PDX and evaluated the effectiveness of HM-001 against low- and high-grade PDX through ex vivo testing. First, patient-derived tissue was transplanted into SCID mice, allowed to grow, and then removed. After extraction, they were cut into 2 mm3 pieces, exposed to HM-001 at 800, 1600, and 3200 ppm for 2 hours, and then transplanted into SCID mice. As a result of comparing the tumor size after transplantation with the control group, a dose-dependent tumor regression effect was confirmed in high-grade and low-grade PDX. NMIBC is divided into low-, medium-, and high-risk categories, with different treatment methods and drugs used for each. In particular, low-grade forms are restricted to low- and intermediate-risk groups. The results of this study show that HM-001 is effective not only for high-risk (including CIS) NMIBC but also for low- and intermediate-risk (low-grade) NMIBC. Citation Format: Shinji Mima, Monta Sakaki, Noriaki Kiya, Atsunari Kawashima, Norio Nonomura, Chihaya Kakinuma. Development of HM-001 as a therapeutic drug for non-muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3329.

Urine-based testing for patient selection and genomic characterization of patients with FGFR alteration-positive non–muscle-invasive bladder cancer (NMIBC) treated with TAR-210.

676 Background: TAR-210 is an intravesical drug delivery system that is designed to provide local, continuous release of erdafitinib. Its safety and efficacy are being evaluated in a first-in-human clinical study (NCT05316155) of patients with bladder cancer whose tumors harbor select FGFR alterations (alt). Toovercome tissue-based challenges in identifying susceptible FGFRalt to select patients for treatment with TAR-210, Janssen partnered with Predicine to use a proprietary urine cell-free DNA diagnostic assay (PredicineCARE). Validation of the urine assay to detect FGFRalt was previously demonstrated using urine samples collected in a highly controlled manner via a collaboration with Stratifyer Molecular Pathology GmbH, Cologne, Germany (Kim et al. ASCO GU 2023). However, evaluation of the urine assay for diagnostic screening in a real-world setting is currently lacking. Here, we report preliminary results of the urine assay for patient selection. We also report on the characterization of the urine-defined genomic landscape in screened patients. Methods: Enrollment was based on detection of prespecified FGFRalt from either tumor tissue obtained from previous biopsies (Qiagen Therascreen FGFR assay) or urine samples obtained prior to enrollment (PredicineCARE next-generation sequencing assay). Results: As of Jun 20, 2023, urine assay performance was compared to the tissue test from all screened patients with NMIBC (N=178). The proportions of samples that yielded results were 60% and 58% from tissue and urine, respectively, while the FGFRalt detection rates in the subsets that yielded results were 62% and 42%, respectively. FGFR3 S249C was the most frequent alteration detected in both tissue (48%) and urine (61%). For 36% of urine samples in which FGFRalt were detected, there was no corresponding tissue result. Of the disease-evaluable patients with high-risk (HR) NMIBC (N=11) or intermediate-risk (IR) NMIBC (N=15),18.2% and 33%, respectively, were enrolled based on urine assay alone due to insufficient tissue samples. A recurrence-free (RF) rate of 82% and a complete response (CR) rate of 87% were achieved at the first disease evaluation amongst patients with HR NMIBC and IR NMIBC, respectively. All patients (HR NMIBC, N=2, and IR NMIBC, N=5) enrolled by “urine only” were RF or achieved a CR. Based on the PredicineCARE panel, comprehensive genomic assessment of urine samples from all screened patients with NMIBC was performed. The prevalence of alterations detected was similar to that described in prior studies using tissue-based testing. Conclusions: Implementing a urine-based assay expands the molecular testing methods to identify additional patients that may respond to erdafitinib. Results justify further study. Clinical trial information: NCT05316155 .

PIVOT-006: A phase 3, randomized study of cretostimogene grenadenorepvec versus observation for the treatment of intermediate risk non-muscle invasive bladder cancer (IR-NMIBC) following transurethral resection of bladder tumor (TURBT).

TPS715 Background: Guidelines for Intermediate Risk Non-Muscle Invasive Bladder Cancer (IR-NMIBC) recommend adjuvant intravesical (IVE) therapy or surveillance. Despite this, 30–60% of patients still recur, and these Guideline recommendations are lacking level-1 evidence. Thus, there is a considerable gap in knowledge and an unmet medical need for improved therapies in the adjuvant setting. Cretostimogene Grenadenorepvec is an oncolytic adenovirus designed to preferentially replicate in and kill cancer cells. The vector is transcriptionally regulated by the E2F promoter that is up-regulated in retinoblastoma (Rb) pathway-defective tumor cells, common in most IR-NMIBC bladder tumors. Additionally, the virus is engineered to selectively express GM-CSF, in order to induce a robust systemic anti-tumor immune response. PIVOT-006 is an open-label, multi-center, randomized Phase 3 study designed to assess the efficacy and safety of intravesical Cretostimogene after TURBT versus TURBT alone. Methods: Eligibility criteria: age ≥18 years, Eastern Cooperative Oncology Group performance status of 0-2, histologically confirmed IR-NMIBC with absence of nodal or metastatic disease at screening. IR-NMIBC, as defined by American Urologic Association-Society of Urologic Oncology Guidelines on NMIBC, is either a Low Grade (LG) stage Ta tumor that recurs within 12 months of prior LG or High Grade (HG) bladder cancer, a solitary LGTa tumor &gt;3cm in size, multifocal LGTa tumors, primary HGTa lesion &lt; 3cm in size, or a LGT1 tumor. Participants will be stratified by receipt of perioperative chemotherapy and tumor grade. Pts (N~450) will be randomized 1:1 to receive intravesical Cretostimogene (Cohort 1) adjuvant to TURBT or TURBT alone (Cohort 2). Single dose perioperative intravesical chemotherapy at the time of TURBT is permitted. If intravesical NMIBC recurrence is noted in Cohort 2, participants will be eligible to receive intravesical Cretostimogene. In Cohort 1, intravesical Cretostimogene will be instilled in combination with n-dodecyl-B-D-maltoside (DDM, an inactive detergent) for 6 weekly doses during the induction phase, followed by 3 weekly maintenance cycles at months 3 and 6, and culminating in single intravesical doses at months 9 and 12. Primary disease assessments include serial cystoscopy, urine cytology, axial imaging, and centralized review of pathologic samples. The primary outcome measure is recurrence free survival. Secondary outcome measures include safety, tolerability, progression free survival, and time to next intervention. Exploratory outcome measures include patient-reported quality of life, biomarker analyses, coxsackie adenovirus receptor and E2F promoter expression, neutralizing antibodies, and markers of immunogenicity. Clinical trial information: Pending.

Guiding adjuvant instillation in intermediate-risk non-muscle invasive bladder cancer by drug screens in patient-derived organoids.

TPS711 Background: Recurrence rates in intermediate risk non-muscle invasive bladder cancer (NMIBC) are high and therefore, clinical guidelines recommend adjuvant instillations. However, the exact regimen with an exact number of instillations and the chemotherapeutic agent to be used are not clearly defined. During the last years we have established a standardized pipeline to generate patient-derived organoids (PDO) from cold cup biopsies of NMIBC. We showed that the subsequent organoids maintain key features of the parental tumor and share the molecular landscape. Moreover, our pipeline allows to investigate drug response to different agents in a standardized manner. Methods: In this ongoing, open-label, single center phase II trial, we aim to use drug screens in PDO of patients with intermediate risk NMIBC to guide drug selection for intravesical instillation. Patients with diagnosis of intermediate-risk NMIBC are enrolled. PDO are generated from biopsies prior transurethral resection of the bladder tumor. On the generated PDO drug response is determined to four chemotherapeutic agents that have already been used for bladder instillations in the literature (Epirubicin, Mitomycin C, Gemcitabine and Docetaxel). The most effective drug is selected for adjuvant instillation into the bladder once weekly for 6 instillations. The follow-up thereafter is performed according to European guidelines. The primary endpoint of the study is to determine the proportion of patients for which a specific selection of chemotherapeutic agent for intravesical instillation can be determined by using drug screens in PDOs. Secondary endpoints are recurrence- and, progression free survival, quality of life and translational studies. The null hypothesis, that a drug prediction will only be possible in 65% of patients, will be tested against a one-sided alternative. Assuming that the real proportion is 85%, 31 participants should show a statistically significant result at 5% significance and 80% power (exact binomial test). Due to early termination of 10%, a total number of 34 patients will be included. We are successfully conducting a trial to implement drug screens in PDO into daily routine and to guide patient treatment. This is a novel concept to precise treatment selection in patients with intermediate-risk NMIBC. When the primary endpoint is met, a modification of the trial with larger sample size, novel compounds and a focus oncological outcomes is foreseen. Clinical trial information: NCT05024734 .

The optimal intravesical maintenance chemotherapy scheme for the intermediate-risk group non-muscle-invasive bladder cancer

ObjectiveAlthough the current European Association of Urology(EAU) guideline recommends that patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC) should accept intravesical chemotherapy or Calmette-Guerin (BCG) for no more than one year after transurethral resection of bladder tumor(TURBT), there is no consensus on the optimal duration of chemotherapy. Hence, we explored the optimal duration of maintenance intravesical chemotherapy in patients with intermediate-risk NMIBC.Subjects and MethodsThis was a real-world single-center retrospective cohort study. In total 158 patients with pathologically confirmed intermediate-risk NMIBC were included, who were divided into 4 subgroups based on the number of instillations given. We used Cox regression analysis and survival analysis chart to explore the 3-yr recurrence outcomes of tumor.The optimal duration was determined by receive operating characteristic curve (ROC).ResultsThe median follow-up was 5.2 years. Compared with instillation for 1–2 months, the Hazard Ratios(HR) values of instillation for less than 1 month, maintenance instillation for 3–6 months and > 6 months were 3.57、1.57 and 0.22(95% CI 1.27–12.41;0.26–9.28;0.07–0.80, P = 0.03;0.62;0.02, respectively). We found a significant improvement in 3-yr relapse-free survival in intermediate-risk NMIBC patients who maintained intravesical instillation chemotherapy for longer than 6 months, and the best benefit was achieved with 10.5 months of maintenance chemotherapy by ROC.ConclusionsIn our scheme, the optimal duration of intravesical instillation with pirrubicin is 10.5 months. This new understanding provides valuable experience for the precise medical treatment model of intermediate-risk NMIBC.

Definitions, End Points, and Clinical Trial Designs for Bladder Cancer: Recommendations From the Society for Immunotherapy of Cancer and the International Bladder Cancer Group.

There is a significant unmet need for new and efficacious therapies in urothelial cancer (UC). To provide recommendations on appropriate clinical trial designs across disease settings in UC, the Society for Immunotherapy of Cancer (SITC) and the International Bladder Cancer Group (IBCG) convened a multidisciplinary, international consensus panel. Through open communication and scientific debate in small- and whole-group settings, surveying, and responses to clinical questionnaires, the consensus panel developed recommendations on optimal definitions of the disease state, end points, trial design, evaluations, sample size calculations, and pathology considerations for definitive studies in low- and intermediate-risk nonmuscle-invasive bladder cancer (NMIBC), high-risk NMIBC, muscle-invasive bladder cancer in the neoadjuvant and adjuvant settings, and metastatic UC. The expert panel also solicited input on the recommendations through presentations and public discussion during an open session at the 2021 Bladder Cancer Advocacy Network (BCAN) Think Tank (held virtually). The consensus panel developed a set of stage-specific bladder cancer clinical trial design recommendations, which are summarized in the table that accompanies this text. These recommendations developed by the SITC-IBCG Bladder Cancer Clinical Trial Design consensus panel will encourage uniformity among studies and facilitate drug development in this disease.

Adjuvant Hyperthermic Intravesical Chemotherapy in Intermediate- and High-Risk Non-muscle Invasive Bladder Cancer.

Non-muscle invasive bladder cancer (NMIBC) is a frequently diagnosed neoplasm, which is typically managed with transurethral resection of bladder tumor (TURBT) eventually followed by intravesical therapies. Bacillus Calmette-Guérin (BCG) is used as first-line adjuvant treatment in high- (HR) and intermediate-risk (IR) NMIBC, although, in the latter, mitomycin C (MMC) may also be used. Multiple limitations to the use of BCG encouraged the search for therapeutic alternatives. In this context, hyperthermic intravesical chemotherapy with MMC (HIVEC-MMC) emerged as a promising therapy in the adjuvant setting for NMIBC. The aim of our study was to evaluate the tolerability, compliance, and survival outcomes of HIVEC-MMC in patients with IR- and HR-NMIBC. This was a single-center retrospective analysis of IR- and HR- NMIBC patients who received HIVEC-MMC after TURBT between August 2018 and August 2022. Levels of risk stratification were defined using the European Association of Urology (EAU) criteria. The protocol consisted of four weekly HIVEC-MMC instillations (induction) followed by six monthly instillations (maintenance). The primary outcomes were to evaluate the tolerability and compliance with the HIVEC-MMC protocol and secondary outcomes were disease-free survival (DFS) and overall survival (OS). For the purpose of statistical analysis, methods of descriptive statistics, survival analysis (Kaplan-Meier estimation), and multivariate analysis (Cox regression, and binary logistic regression) were used. Fifty-seven patients were enrolled with a median age of 67.9 (34.4-83.5) years old. In this cohort, 40 patients (70.2%) had primary tumors. At the time of referral for HIVEC-MMC, the majority of the patients had IR-NMIBC (n= 33, 57.9%). A total of 41 patients (71.9%)completed the HIVEC-MMC protocol. Disease recurrence and adverse events (AEs) were the most common reasons to stop the protocol. After a median follow-up of 31 months (95% CI, 5.0-54.0), 32 patients (61.4%) were disease-free, 22 (38.6%) experienced recurrent disease and six patients (10.5%) died, although only one death was directly attributable to bladder cancer. The median DFS was 42 months (95% CI, 28.0-56.0). Completion of the HIVEC-MMC maintenance phase protocol stood as a predictive factor for DFS (44 months, 95% CI 29.1-58.9 vs. 14 months, 95% CI 0.0-29.6, p < 0.001; HR 4.48, 95% CI 1.65-12.15). The median OS was not reached; the 24- and 48-monthOS were 92.6% and 82.7%, respectively. EAU risk group, ECOG-PS, and completion of HIVEC protocol were found to be significant predictive factors of OS but lost their significance on multivariate analysis. However, if we exclude those who experienced recurrence during the maintenance phase protocol, treatment completion had a significant positive impact on OS (HR: 42.8, 95% CI 1.75-1045.072, p= 0.021). Our study suggests that HIVEC is a secure and well-tolerated treatment with promising efficacy data, making this therapeutic approach a feasible option in IR- and HR-NMIBC patients, mainly in those who cannot tolerate or have contraindications to BCG therapy, but also as an alternative during BCG shortages.

International Bladder Cancer Group Intermediate-risk Non-muscle Invasive Bladder Cancer (IBCG IR-NMIBC) Scoring System Predicts Outcomes of Patients on Active Surveillance.

To determine if the International Bladder Cancer Group (IBCG) intermediate risk (IR)-NMIBC scoring system can predict the requirement of delayed transurethral resection of bladder tumor (TURBT) in low grade (LG) non-muscle invasive bladder cancer (NMIBC) managed by active surveillance (AS). A prospective study of recurrent LG Ta/T1 NMIBC patients managed with AS with the following characteristics were used: LG papillary NMIBC, ≤5 apparent LG NMIBC, tumor diameter ≤1 cm, absence of gross hematuria and negative urinary cytology. Subsequent TURBT was offered to patients who no longer met the inclusion criteria or patient choice. The ability of the IBCG IR-NMIBC scoring system to predict receipt of subsequent TURBT was determined. Multivariable Cox proportional-hazards analysis was used to determine factors associated with subsequent TURBT. A total of 163 patients with LG Ta/T1 NMIBC were included for analysis. After a median follow-up of 33 months (21-46), TURBT was performed on 109 patients. At landmark timepoint of 24 months, patients with 0 RF factors were over two-fold more likely to continue AS compared to patients with ≥3 RF (59% versus 24%). Multivariable Cox regression suggest that the IBCG IR-NMIBC scoring system was associated with subsequent TURBT (1-2 RF [HR: 1.66, 95% CI: 0.96-2.90, P = .072], ≥3 RF [HR: 3.21, 95% CI: 1.70-6.09, P < .001]) after adjusting for age, T-stage and sex. The IBCG IR-NMIBC scoring system can predict the risk of a subsequent TURBT in patients with LG NMIBC on AS.

Sequential intravesical gemcitabine and docetaxel for treatment-naïve and previously treated intermediate-risk nonmuscle invasive bladder cancer

IntroductionAdjuvant intravesical therapy is recommended for patients with intermediate-risk NMIBC. While intravesical gemcitabine-docetaxel (Gem/Doce) has demonstrated favorable outcomes for high-risk NMIBC, its utility in the intermediate-risk setting is not well described. We report outcomes of Gem/Doce as an adjuvant treatment for intermediate-risk NMIBC. MethodsWe retrospectively identified patients with intermediate-risk NMIBC by AUA criteria treated with Gem/Doce following TURBT between 2012 and 2022. Patients received weekly sequential intravesical instillations of 1 g gemcitabine and 37.5 mg docetaxel for 6 weeks. Monthly maintenance of 2 years was initiated if disease-free at first surveillance. The primary outcome was recurrence-free survival (RFS), assessed using the Kaplan-Meier method. ResultsThe cohort included 77 patients with median follow-up of 26 (IQR 14–50) months. Prior to induction, 67 (87%) patients presented with Ta low-grade (LG) lesions, 3 (3.9%) with Ta high-grade (HG), 5 (6.5%) with TaLG plus focal TaHG, and 2 (2.6%) with T1LG. Thirty-three (43%) patients received previous intravesical therapy including BCG (23), mitomycin (13), and docetaxel monotherapy (12). The 2-year RFS was 71% among all patients. Treatment-naïve patients had superior RFS compared to previously treated patients (P = 0.04); 2-year estimates were 79% and 64%, respectively. Twenty-nine (38%) patients experienced adverse events; all were Grade 1 to 2 except 1 (1.3%) Grade 3 (acute oxygen desaturation). Three (3.9%) patients did not tolerate a full induction course. ConclusionsIn this retrospective review of a heterogenous population of patients with intermediate-risk NMIBC, Gem/Doce was an effective and well-tolerated adjuvant therapy. Further prospective evaluation in this setting is needed.

Electromotive Drug Administration Chemotherapy with Mitomycin C Versus Bacillus Calmette-Guerin for the Treatment of Non-Muscle Invasive Bladder Cancer

BACKGROUND: Devices that increase the penetrance of intravesical chemotherapeutics are emerging as alternatives to classical Bacillus Calmette Guérin (BCG) treatment. OBJECTIVE: To compare the efficacy of mitomycin C applied with the electromotive drug delivery device (MMC-EMDA) versus BCG in patients with intermediate and high-risk non-muscle-invasive bladder cancer (NMIBC) without carcinoma in situ (CIS). METHODS: Prospective non-randomized study in which 47 patients received MMC-EMDA (40 mg of MMC diluted in 50 mg of distilled water at 20 mA for 30 min. Regimen of 6 weekly and then 6 monthly instillations) and 48 patients received BCG (50 mg of OncoCITE® diluted in 50 ml of normal saline for 60 min. Regimen of 6 weekly instillations and then 3 weekly instillations at months 3, 6 and 12). The primary endpoint was the recurrence-free rate (RFR) at 24 months. Secondary endpoints were time to recurrence and progression-free rate (PFR) at 24 months follow-up. RESULTS: Baseline patient assessment and mean follow-up time were similar in both groups (MMC-EMDA group: 26.4 months; BCG group: 28.4 months (p = 0.44)). The RFR at 24 months was 80.9% for the MMC-EMDA group and 77.1% for the BCG group (p = 0.969). The mean time to recurrence was 12.5 months in the MMC-EMDA group and 14 months in the BCG group (p = 0.681). At 24 months, PFR was 97.9% in the MMC-EMDA group and 93.8% in the BCG group (p = 0.419). CONCLUSIONS: No differences were found between MMC-EMDA and BCG treatments in patients with high-risk and intermediate-risk NMIBC without CIS.

Guidance of adjuvant instillation in intermediate-risk non-muscle invasive bladder cancer by drug screens in patient derived organoids: a single center, open-label, phase II trial

BackgroundIn intermediate-risk non-muscle invasive bladder cancer (NMIBC) clinical guidelines suggest an adjuvant instillation with a chemotherapeutic agent. However, the agent and regimen are not clearly defined. Worldwide, less than 15% of patients receive this adjuvant chemotherapeutic instillation. We recently developed a pipeline for the generation of patient derived organoids (PDO) in NMIBC. In this phase II trial, we aim to use our in vitro pipeline to select the most effective drug for chemotherapeutic instillation in NMIBC patients.MethodsPatients with first diagnosis of intermediate-risk NMIBC that are directed to transurethral resection of bladder tumor (TURBT) are enrolled. During TURBT, tumor is sampled, and specimens are directed to generate PDO. Once the PDO are formed, drug screens on them for Epirubicin, Mitomycin C, Gemcitabine and Docetaxel are performed. The drug with the highest antitumor activity in vitro will then be selected for 6 adjuvant intravesical instillations once weekly. Thereafter, patients are followed according to clinical guidelines by cystoscopy.DiscussionThe aim of this trial is to use drug screens in PDO to precise treatment selection for adjuvant instillation therapies in patients with intermediate-risk NMIBC. The ultimate goal of this trial is to reduce the risk of cancer recurrence. In the future, we aim to conduct clinical multicenter trials with an increased sample size, a broader panel of compounds and a focus on the reduction of cancer recurrence by precision delivery of care.Trial registration NCT05024734.

Surveillance of Low-Grade Non-Muscle Invasive Bladder Tumors Using Uromonitor: SOLUSION Trial

The surveillance of non-muscle invasive bladder cancer (NMIBC) requires frequent cystoscopies, which are costly and uncomfortable for patients. Uromonitor is a validated non-invasive urinary test for detecting NMIBC recurrence. However, data on its clinical benefit in an NMIBC surveillance program is limited. To assess the diagnostic accuracy of Uromonitor in NMIBC surveillance and its potential to limit the number of cystoscopies. The study included 202 patients with previous low-grade (LG) NMIBC tumors. Newly diagnosed patients were scheduled for flexible cystoscopy and Uromonitor test at 4, 12, and 24 months from the time of diagnosis. Patients with tumors diagnosed before entering the study underwent cystoscopy and Uromonitor test at the start of the study and 12 and 24 months from inclusion in the study. Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV). Between February 2020 and October 2022, 202 patients were enrolled in the study. Of these patients, 171 met the eligibility criteria to perform the analysis, with a median age of 69 years, IQR (62-74), and 380 flexible cystoscopies with simultaneous Uromonitor tests. Overall, 39/171 (22.8%) patients had recurrences. Uromonitor showed a sensitivity of 89.7%, specificity of 96.2%, PPV of 72.9%, and NPV of 98.8%. In 28 cases, flexible cystoscopy was falsely positive, leading to surgery, where Uromonitor showed negative results. There were 13 cases of possible false positives for Uromonitor where flexible cystoscopy was negative. Uromonitor displays high diagnostic accuracy in detecting NMIBC recurrence with the potential for reducing the number of flexible cystoscopies in the follow-up of low- and intermediate-risk NMIBC. We followed up on newly and previously diagnosed patients with LG NMIBC. We concluded that Uromonitor could potentially reduce the number of cystoscopies in NMIBC surveillance programs.

MP08-14 LONG TERM OUTCOMES OF REPEATED MITOMYCIN C INSTILLATION IN LOW RISK AND INTERMEDIATE RISK NON-MUSCLE INVASIVE BLADDER CANCER PATIENTS

You have accessJournal of UrologyCME1 Apr 2023MP08-14 LONG TERM OUTCOMES OF REPEATED MITOMYCIN C INSTILLATION IN LOW RISK AND INTERMEDIATE RISK NON-MUSCLE INVASIVE BLADDER CANCER PATIENTS Pietro Scilipoti, Mattia Longoni, Mario de Angelis, Chiara Re, Giuseppe Rosiello, Alessandro Bertini, Giulio Avesani, Donato Cannoletta, Giorgio Gandaglia, Umberto Capitanio, Andrea Salonia, Francesco Montorsi, Alberto Briganti, and Marco Moschini Pietro ScilipotiPietro Scilipoti More articles by this author , Mattia LongoniMattia Longoni More articles by this author , Mario de AngelisMario de Angelis More articles by this author , Chiara ReChiara Re More articles by this author , Giuseppe RosielloGiuseppe Rosiello More articles by this author , Alessandro BertiniAlessandro Bertini More articles by this author , Giulio AvesaniGiulio Avesani More articles by this author , Donato CannolettaDonato Cannoletta More articles by this author , Giorgio GandagliaGiorgio Gandaglia More articles by this author , Umberto CapitanioUmberto Capitanio More articles by this author , Andrea SaloniaAndrea Salonia More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Alberto BrigantiAlberto Briganti More articles by this author , and Marco MoschiniMarco Moschini More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003223.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The use of repeated Mitomycin C (MMC) instillation in low- (LR) and intermediate-risk (IR) Non-Muscle Invasive Bladder Cancer (NMIBC) is still a matter of discussion among the urological community. The aim of the current study was to analyze long term outcomes of maintenance regimen of repeated MMC instillations in LR and IR patients. METHODS: We identified 228 patients diagnosed with NMBIC after transurethral resection of bladder tumor (TURBT) that underwent MMC instillations between 2013 and 2022 at a tertiary referral center. All patients felt within the criteria for LR or IR class according to European Association of Urology Guidelines. Recurrence-free survival (RFS) was analyzed and compared with Cox-derived univariate Kaplan-Meier (KM). A Multivariable Cox-regression analyses (MVA) assessed the impact of MMC maintenance regimen on RFS (covariates: T stage, grade, multifocality, early instillation). Subgroup analysis evaluated the effect of MMC instillations number on RFS in patients who received maintenance. RESULTS: Overall, 89 (39%) and 139 (61%) patients were diagnosed with LR and IR NMIBC, respectively. Low grade lesions were found in 88% (n=200) of cases. Pathological Ta tumors were 93% (n=211) and multifocality was present in 107 cases (47%). Median age at diagnosis and follow-up time were 71 (IQR 62-77) and 44 months (IQR 28-63), respectively. Early instillation was performed in only 21 patients (9.2%). Recurrence occurred in 57 patients (25%). All patients underwent MMC induction with 89% rate of 6-instillations cycle completion; 118 patients (51%) underwent maintenance instillations with a median number of instillations equal to 9.5 (6-11). Overall, RFS at 5 years follow-up was 69.6% [62.7, 77.2]. Patients who did or did not receive MMC maintenance had a 5-years RFS of 73.4% vs 65.2%. At MVA, MMC maintenance and number of instillations did not significantly correlate with a better RFS. CONCLUSIONS: Our study showed that MMC maintenance instillations do not reduce the risk of recurrence in LR and IR NIMBC patients who received MMC induction. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e99 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Pietro Scilipoti More articles by this author Mattia Longoni More articles by this author Mario de Angelis More articles by this author Chiara Re More articles by this author Giuseppe Rosiello More articles by this author Alessandro Bertini More articles by this author Giulio Avesani More articles by this author Donato Cannoletta More articles by this author Giorgio Gandaglia More articles by this author Umberto Capitanio More articles by this author Andrea Salonia More articles by this author Francesco Montorsi More articles by this author Alberto Briganti More articles by this author Marco Moschini More articles by this author Expand All Advertisement PDF downloadLoading ...

Phase 2 study of the efficacy and safety of erdafitinib in patients (pts) with intermediate-risk non–muscle-invasive bladder cancer (IR-NMIBC) with FGFR3/2 alterations (alt) in THOR-2: Cohort 3 interim analysis.

504 Background: Current treatments (tx) of papillary NMIBC are not selective. Novel tx can be assessed on measurable disease (eg, a marker lesion) to rapidly and directly assess antitumor efficacy. FGFR inhibitor therapy may improve outcomes for pts with IR-NMIBC with FGFR3/2alt. Erdafitinib (erda) is an oral selective pan-FGFR tyrosine kinase inhibitor approved for locally advanced or metastatic urothelial cancer in adults with FGFR3/2alt who have progressed during or following ≥1 line of platinum-containing chemotherapy. THOR-2 (NCT04172675) is a multicohort phase 2 study of erda in pts with NMIBC. We report results in an exploratory cohort of pts with IR-NMIBC with FGFRalt (Cohort 3). Methods: Inclusion: age ≥18 y, with histologically confirmed NMIBC with FGFR3/2alt (local/central testing) and recurrent IR disease, with all previous tumors being low grade (Gr) (Gr 1-2), Ta/T1, no previous carcinoma in situ, risk of progression &lt;5% in the next 2 y, and risk of recurrence &gt;50%. All tumors were removed by transurethral resection of bladder tumor except for a marker lesion (single untouched 5-10 mm lesion). Pts received continuous oral erda 6 mg once daily without uptitration in 28-d cycles. Urine cytology was performed at the time of complete response (CR). Pts with a partial response (PR) or CR ≤3 mos of starting erda continued erda for up to a maximum of 2 y, until progressive disease, intolerable toxicity, withdrawal of consent, investigator decision to discontinue tx, or study closure. Primary exploratory end point: CR rate (CR = disappearance of the marker lesion without any new lesions; if there is a remnant of the marker lesion, no viable tumor should be seen on histopathological examination); key secondary end point: safety. Results: As of the data cutoff (Sep 2022) (median follow-up of 6.2 mos), 10/11 enrolled pts have received erda (enrolled population; median age: 66 y [range 47-77]; 9 Ta, 2 not staged). Pts received erda for a median duration of 2.9 mos (range 1.1-8.4). Efficacy (n=8 evaluable): 6 pts had CR (CR rate, 75.0%; 95% CI, 34.9-96.8%), and 1 had PR. Of 7 pts with CR or PR, median observed duration of response was 2.8 mos. Safety (≥1 dose of erda; n=10): the most common tx-emergent adverse events (TEAEs) were hyperphosphatemia (90.0%; n=9), diarrhea (60.0%; n=6), dry mouth (50.0%; n=5), dry skin (30.0%; n=3), dysgeusia (30.0%; n=3), and constipation (30.0%; n=3). One pt had Gr ≥3 dysuria (10.0%) and 1 (10.0%) had Gr ≥3 tx-related diarrhea. One pt (10.0%) had Gr 1 tx-related central serous chorioretinopathy. No pts had tx-related serious TEAEs or tx-related TEAEs leading to discontinuation. No deaths occurred. Conclusions: Data from Cohort 3 of THOR-2 demonstrate efficacy in adult pts with IR-NMIBC with FGFRalt. Safety data were consistent with the known safety profile of erda. Clinical trial information: NCT04172675 .

Safety and efficacy of the erdafitinib (erda) intravesical delivery system, TAR-210, in patients (pts) with non–muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC) harboring select FGFR mutations or fusions: Phase 1 first-in-human study.

TPS583 Background: Treatment options are limited for pts with NMIBC and MIBC who experience disease recurrence or who are ineligible for or refuse standard of care. Erda, an oral selective pan-FGFR tyrosine kinase inhibitor, is approved in adults with locally advanced or metastatic urothelial cancer with select FGFR3/2 alterations ( alt) who have progressed during or after ≥1 line of platinum-containing chemotherapy. FGFRalt are among the most common oncogenic drivers detected in NMIBC and MIBC, and are more prevalent in NMIBC. TAR-210 is an intravesical drug delivery system designed to provide local, continuous release of erda within the bladder, thus limiting systemic toxicity. This study evaluates the safety, pharmacokinetics (PK), and efficacy of TAR-210 in pts with NMIBC or MIBC with select FGFRalt. Methods: Open-label, multicenter phase 1 study of TAR-210 in pts with recurrent NMIBC or MIBC (NCT05316155). Eligible pts are aged ≥18 yrs with adequate organ function and tumors with select FGFRalt. A flexible molecular eligibility strategy is used to allow for local or central fresh/archival tissue-based FGFR testing by next-generation sequencing (NGS) or PCR, or urine cell-free DNA NGS testing. Four cohorts will be enrolled: pts with recurrent, bacillus Calmette-Guerin (BCG)-experienced papillary-only high-risk (HR) NMIBC (high-grade Ta/T1) refusing or ineligible for radical cystectomy (RC) (Cohort 1) or scheduled for RC (Cohort 2); pts with recurrent, intermediate-risk NMIBC (Ta/T1) with a history of low-grade disease (Cohort 3); pts with cT2-T3a MIBC scheduled for RC refusing or ineligible for neoadjuvant cisplatin (Cohort 4). Pts in Cohorts 1 and 2 will have TURBT with resection of all visible disease prior to dosing, whereas pts in Cohort 3 must have visible disease prior to dosing. The primary end point is safety (adverse events, including dose-limiting toxicity). Secondary end points include PK, recurrence-free survival (Cohorts 1 and 2), complete response (CR) rate and duration of CR (Cohort 3), and pathologic CR rate, pT0 rate, and rate of downstaging to &lt;pT2 (Cohort 4). Dose escalation (Part 1; n≈12, Cohorts 1 and 3 only) will be followed by dose expansion (Part 2; n≈50-80). Cohorts 1 and 3: response assessment will be after a 3-mo dosing cycle; pts with CR may receive ≤3 additional 3-mo dosing cycles if no recurrence, progression, or unacceptable toxicity. Cohorts 2 and 4: response assessment will be at RC after 8 wks of dosing. Follow-up disease surveillance (cystoscopy, urine cytology, imaging) will be every 3 mos to end of Yr 2 and every 6 mos in Yr 3 in Cohorts 1 and 3 and at 3 mos post-RC in Cohorts 2 and 4. Four pts were enrolled since April 2022 (1 in Cohort 1, 3 in Cohort 3); enrollment for Cohorts 2 and 4 is planned soon. Clinical trial information: NCT05316155 .

Natural History of Multiple Recurrences in Intermediate-Risk Non-Muscle Invasive Bladder Cancer: Lessons From a Prospective Cohort

ObjectiveTo describe the risk of multiple recurrences in intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) and their impact on progression. Prognostic studies of IR-NMIBC have focused on initial recurrences, yet little is known about subsequent recurrences and their impact on progression. Materials and MethodsIR-NMIBC patients from the Be-Well Study, a prospective cohort study of NMIBC patients diagnosed from 2015 to 2019 at Kaiser Permanente Northern California, were identified. The frequency of first, second, and third intravesical recurrences of urothelial carcinoma were characterized using conditional Kaplan-Meier analyses and random-effects shared-frailty models. The association of multiple recurrences with progression was examined. ResultsIn 291 patients with IR-NMIBC (median follow-up 38 months), the 5-year risk of initial recurrence was 54.4%. After initial recurrence (n = 137), 60.1% of patients had a second recurrence by 2 years. After second recurrence (n = 70), 51.5% of patients had a third recurrence by 3 years. In multivariable analysis, female sex (Hazard Ratio 1.51, P< .01), increasing tumor size (HR 1.14, P< .01) and number of prior recurrences (HR 1.24, P< .01) were associated with multiple recurrences; whereas maintenance BCG (HR 0.66, P = .03) was associated with reduced recurrences. The 5-year risk of progression varied significantly (P< .01) by number of recurrences: 9.5%, 21.9%, and 37.9% for patients with 1, 2, and 3+ recurrences, respectively. ConclusionsMultiple recurrences are common in IR-NMIBC and are associated with progression. Female sex, larger tumors, number of prior recurrences, and lack of maintenance BCG were associated with multiple recurrences. Multiple recurrences may prove useful as a clinical trial endpoint for IR-NMIBC.

Hyperthermic Mitomycin C in Intermediate-risk Non–muscle-invasive Bladder Cancer: Results of the HIVEC-1 Trial

BackgroundOptimising therapeutic strategies of intermediate-risk non–muscle-invasive bladder cancer (IR-NMIBC) is needed. ObjectiveTo compare recurrence-free survival (RFS) with adjuvant intravesical mitomycin C (MMC) at normothermia or hyperthermia using the COMBAT bladder recirculation system at 43 °C for 30 and 60 min. Design, setting, and participantsA prospective open-label, phase 3 randomised controlled trial (HIVEC-1) accrued across 13 centres between 2014 and 2020 in Spain. After complete transurethral resection of the bladder and immediate postoperative MMC instillation, patients with IR-NMIBC were randomised (1:1:1) to four weekly followed by three monthly 40-mg MMC instillations at normothermia (control; n = 106), 43 °C for 30 min (n = 107), or 43 °C for 60 min (n = 106) were investigated. Therapeutic compliance was defined as four or more instillations. Outcome measurements and statistical analysisThe primary outcome was RFS at 24 mo in the intention-to-treat (ITT) and per-protocol (PP) populations. The secondary outcomes included progression-free survival at 24 mo, safety outcome measures, and changes in health-related quality of life. Log-rank, Fisher, χ2, and analysis of variance tests were used. Results and limitationsThe ITT 24-mo RFS was 77% for control, 82% for 43 °C-30 min, and 80% for 43 °C–60 min (p = 0.6). The PP 24-mo RFS was 77% for control, 83% for 43 °C–30 min, and 80% for 43 °C-60 min (p = 0.59). Six patients progressed to muscle-invasive disease in the ITT population (four in the control, 43 °C–30 min, and 43 °C–60 min groups each) and four in the PP population (all controls). Serious adverse events occurred in 26 patients (8.1%), and we were unable to demonstrate a difference between groups (p = 0.5). Adverse events, mainly dysuria and spasms, occurred in 124 patients (33% in control, 35% in 43 °C–30 min, and 48% in 43 °C–60 min; p = 0.05). The total International Prostate Symptom Score worsened by 1.2 ± 7.3 points, similarly across groups (p = 0.29). The Functional Assessment of Cancer Therapy—Bladder domains and indexes showed no significant change. ConclusionsFour-month adjuvant hyperthermic MMC using the COMBAT system for 30 and 60 min in IR-NMIBC is well tolerated, but we did not find it to be superior to normothermic MMC at 24 mo. Patient summaryWe were unable to demonstrate the effectiveness of hyperthermia using the COMBAT system in intermediate-risk non–muscle-invasive bladder cancer. Further evaluation of long-term recurrence and progression, and maintenance regimens appears mandatory.