NCCN Guidelines® Insights: Bladder Cancer, Version 3.2024.

MAINTENANCE BACILLUS CALMETTE-GUERIN IMMUNOTHERAPY FOR RECURRENT TA, T1 AND CARCINOMA IN SITU TRANSITIONAL CELL CARCINOMA OF THE BLADDER: A RANDOMIZED SOUTHWEST ONCOLOGY GROUP STUDY

EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2013 Guidelines

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 .

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The goal of this article is to provide recommendations for the diagnosis and treatment of muscle-invasive and metastatic bladder cancer. The diagnosis of muscle-invasive bladder cancer is made by pathologic evaluation after transurethral resection. Recently, a molecular classification has been proposed. Staging of muscle-invasive bladder cancer must be done by computed tomography scans of the chest, abdomen and pelvis and classified on the basis of UICC system. Radical cystectomy and lymph node dissection are the treatment of choice. In muscle-invasive bladder cancer, neoadjuvant chemotherapy should be recommended in patients with good performance status and no renal function impairment. Although there is insufficient evidence for use of adjuvant chemotherapy, its use must be considered when neoadjuvant therapy had not been administered in high-risk patients. Multimodality bladder-preserving treatment in localized disease is an alternative in selected and compliant patients for whom cystectomy is not considered for clinical or personal reasons. In metastatic disease, the first-line treatment for patients must be based on cisplatin-containing combination. Vinflunine is the only drug approved for use in second line in Europe. Recently, immunotherapy treatment has demonstrated activity in this setting.

Non muscle invasive bladder cancer (NMIBC) comprises almost 75% of all bladder cancer (BC) diagnoses. Longstanding intravesical treatment options include chemotherapy or Bacillus Calmette-Guerin (BCG). However, despite these treatment options, there is a high rate of relapse for NMIBC patients, reaching up to 40–50% for patients with high risk disease. Radical cystectomy is recommended by guideline committees for patients with high risk NMIBC and for patients who fail intravesical treatment options however this is a procedure with high morbidity and many patients are not good candidates or prefer more conservative treatment approaches. Given this and the high failure rates of current therapies, much ongoing research in NMIBC is focused on other bladder sparing treatment modalities. There have been new advances in molecular features of BC with findings of genetic alterations in NMIBC leading way to a rise in precision medicine targeting a patient’s individual gene mutation. While data surrounding these targeted therapies in NMIBC specifically are all preliminary, many trials are currently underway derived from success in targeted treatments for locally advanced or metastatic BC. Preliminary results are promising and the targeted therapies for NMIBC are increasing. We performed a PubMed and Medline (OVID) literature review assessing recently published studies on targeted therapy on NMIBC, and an additional search on clinicaltrials.gov for active clinical trials. We report on preliminary outcomes and ongoing later stage trials for targeted therapies in NMIBC and anticipate upcoming promising changes to the treatment landscape.

El cáncer vesical (BC) continúa siendo un reto en la práctica clínica urológica actual. Es el séptimo tumor más frecuente diagnosticado en varones a nivel mundial y el 11º si tenemos en cuenta ambos sexos. Ya desde el abordaje del tumor vesical no músculo invasivo (NMIBC) existen limitaciones en el tratamiento: resección transuretral no siempre completa, fracasos o recidivas precoces tras el tratamiento con BCG así como efectos secundarios que obligan a la suspensión de la misma. En el tratamiento del tumor vesical músculo invasivo (MIBC) la cistectomía radical no es una opción para todos los pacientes debido a la importante comorbilidad perioperatoria. En los pacientes con tumores vesicales metastásicos, los efectos secundarios de la quimioterapia convencional, así como la progresión tumoral, ha suscitado una necesidad de desarrollar nuevas líneas terapéuticas. Los avances en el conocimiento de la biología molecular oncológica, han posibilitado encontrar nuevas dianas terapéuticas (como los inhibidores del ciclo celular) y mediante el empleo de anticuerpos monoclonales, desarrollar fármacos específicos dirigidos contra ellas. Actualmente hay cinco fármacos aprobados por la FDA y la EMA para el tratamiento en el cáncer vesical musculoinvasivo metastásico, entre los cuales destacan atezolizumab, nivolumab y pembrolizumab por su mayor implantación en la práctica clínica. Los buenos resultados obtenidos en el cáncer vesical metastásico, han provocado el desarrollo de nuevas líneas de investigación para el empleo de estas moléculas en estadíos más precoces de la enfermedad y en protocolos de neoadyuvancia. Así mismo, se están realizando múltiples estudios sobre la combinación de estos nuevos agentes con quimioterapia convencional y radioterapia para determinar los esquemas de tratamiento más adecuados. En este trabajo recogemos de manera sucinta el estado actual de la inmunoterapia en el cáncer vesical.

556 Background: Elaborate treatment and repetitive surveillance makes bladder cancer to the most expensive cancer type over the lifetime of a patient with a peak in non-muscle invasive bladder cancer. Radical cystectomy (RC) as the Standard of Care in BCG unresponsive NMIBC is associated with a significant health-related quality-of-life burden (QALY). Gemcitabine/Docetaxel, Pembrolizumab or Hyperthermic Intravesical Chemotherapy (HIVEC) have recently been published as salvage treatment options trying to increase the rate of bladder preservation. Methods: We developed a Markov model from a payer´s perspective with the clinical data of single-arm studies for BCG unresponsive NMIBC (Gemcitabine/Docetaxel and Pembrolizumab) and our clinical data for patients receiving HIVEC (n=29) as intravesical salvage-chemotherapy. Costs were simulated with a non-commercial DRG-grouper, utilities were derived from comparable cost-effectiveness studies. We used a Monte-Carlo Simulation to identify the optimal treatment, comparing the incremental cost effectiveness ratios (ICER) in consideration of a willingness-to pay of 50.000 Euro/QALY. Results: Over a horizon of 10 years, Gemcitabine/Docetaxel, HIVEC and Pembrolizumab were associated with costs of 48.353 64.438 and 204.580 Euro, and QALY´s of 6.16, 6.48 and 6.00, resulting in an ICER of 26.482, 42.567 and 184.533 Euro in comparison to RC (costs: 21.871 Euro; QALY: 5.01). Monte-Carlo Simulation has identified HIVEC as the treatment of choice in the assumption of a WTP of <50.000 Euro. QALY gains in Gemcitabine/Docetaxel and especially HIVEC were mainly driven by bladder preservation and the low rate of progression. Conclusions: Considering a WTP of <50.000 Euro / QALY, Gemcitabine/Docetaxel and HIVEC are highly cost-effective therapy options in BCG unresponsive bladder cancer, while RC remains the cheapest option. At its current price, Pembrolizumab is only cost-effective with a price reduction of 70%.

Platelet-Derived Growth Factor Receptor Expression and Activation in Choroid Plexus Tumors

On December 16, 2022, the FDA approved the adenoviral vector-based gene therapy nadofaragene firadenovec-vncg (brand name Adstiladrin) for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS). The product represents the first approved adenoviral vector-based gene therapy and the first approved gene therapy for bladder cancer. Determination of efficacy was based on results from Study rAd-IFN-CS-003 (Study CS-003), a single-arm trial in 98 evaluable patients with BCG-unresponsive NMIBC with CIS who received intravesical instillations of the gene therapy product (75 mL of nadofaragene firadenovec at 3 × 1011 viral particles per mL) once every 3 months. The major efficacy outcome measures were complete response (CR) at any time and duration of response. Fifty subjects experienced CR 3 months after the initial treatment (CR = 51%; 95% confidence interval, 40.7; 61.3%), of whom 46% remained in response for ≥12 months. The median duration of response was 9.7 months (range: 3-52+). Common adverse reactions included instillation site discharge, fatigue, bladder spasm, micturition urgency, hematuria, chills, pyrexia, and dysuria. The approval of nadofaragene firadenovec provides a new therapy option for patients with BCG-unresponsive NMIBC with CIS who are ineligible for cystectomy.

Combinations of Urinary Biomarkers for Surveillance of Patients with Incident Nonmuscle Invasive Bladder Cancer: The European FP7 UROMOL Project

Development of the First Patient-centred Set of Outcomes for Muscle-invasive and Metastatic Bladder Cancer: A Multicentre Initiative

Bladder cancer is the 7th most commonly diagnosed cancer in males worldwide and the 11th when both genders are considered. Seventy five per cent of bladder cancer cases are non-muscle invasive bladder cancer (NMIBC). Bacillus Calmette–Gu rin (BCG) immunotherapy remains the standard intravesical agent for NMIBC. The exact mechanism by which BCG prevents recurrence is unknown. The aim of this study was to evaluate NLR4 gene expression and IL-1β as possible prognostic indicators for NMIBC recurrence and BCG treatment failure, and to detect the difference in their levels among muscle invasive bladder cancer (MIBC) and NMIBC that may aid in primary differentiation between cases. This study was conducted in 30 patients who had NMIBC and 17 patients who had MIBC. Urine samples were obtained in sterile cups before operation. From NMIBC cases, four more samples were obtained as mentioned below. Evaluation of NLR4 gene expression was performed in pre-surgical sample for MIBC and in 4 samples for NMIBC: pre-surgical sample, sample collected 4 hours after the 3rd dose of BCG instillation, and samples collected during follow up (3 and 6 months post-surgically). There was statistical significant increase in NLRP4 expression levels in NMIBC (CT=0.87±1.48) compared to MIBC (CT=2.82±2.07). As far as we searched, no published results were found regarding comparative gene expression levels between NMIBC and MIBC cases. Gene expression in recurrent cases was higher in pre-surgical urine samples than in non-recurrent cases. The expression level further increased up to 21 fold than the pre-surgical level in the sample taken after injection of the 3rd dose of BCG. This level decreased distinctly to become 1-fold increase over pre-surgical level at the 3rd month follow up then to only 0.9-fold at the 6th month. In non- recurrent cases, gene expression level started pre-surgically in much lower levels than those encountered in recurrent cases. There were 11-fold increase in expression level after 3rd dose of BCG instillation and then decreased to be 5.6 folds higher in the sample taken at 3rd month follow up than in presurgical samples. Gene expression further decreased to become 4.1 fold higher in samples taken at 6 month follow up than the pre-surgical levels. IL-1β levels were estimated for NMIBC and MIBC cases in urine samples pre-surgically and during BCG therapy in case of NMIBC before and 4 hours after the 3rd dose and during 3rd month follow-up of those cases for searching its possible use of for primary differentiation between NMIBC and MIBC, and also as a prognostic factor for possible recurrence in case of NMIBC cases. The level of IL-1β was generally higher in pre-surgical samples (0.62±0.12 pg/ml) when compared to its level before the 3rd dose of BCG induction therapy (0.53±0.13 pg/ml). Its level was distinctly higher four hours after administration of the 3rd dose BCG (1.96±0.62 pg/ml) than both previous levels. Levels decreased bellow pre-surgical level at 3rd month follow up (0.57±0.099 pg/ml). The levels of IL-1β estimated in samples collected four hours after the 3rd dose BCG was higher in cases that showed recurrence later on than non-recurrent cases. The levels decreased in both cases and became higher in non-recurrent cases (0.64±0.05 pg/ml) than in cases already developed recurrence at the 3rd month diagnosed during follow-up (0.45±0.05 pg/ml). To conclude, on following NLRP4 gene expression and IL-1β levels during BCG administration among recurrent and non-recurrent cases of thirty NMIBC cases, there was a significant statistical difference in both levels for the samples collected after the third dose BCG, being higher in patients who showed subsequent recurrence at the 3rd and 6th month of follow-up. If these preliminary reported findings will be confirmed in upcoming larger cohort’s studies, it could be promising in prognosis of such cases, with the possibility of early manipulation of individualized treatment schedule, keeping patients most probably prone to encounter recurrence safe from possible side effects of BCG therapy. The assessment of NLRP4 expression and IL-1β levels could help predict failure of BCG therapy, playing an appreciable role in early deciding radical surgery. When comparing NLRP4 expression and IL-1β levels between MIBC and NMIBC cases, increased values were noted among non-invasive ones. This finding may serve as a possible diagnostic tool, which represents a challenging issue. Hence, cut-off values for gene expression and cytokine level are to be specified.

Background: Bladder cancer is the 5th most common cancer worldwide, with the most common type being non-muscle invasive bladder cancer (NMIBC). Treatment for high grade NMIBC includes resection of the bladder tumor followed by repeated intravesical administration of Bacillus-Calmette Guérin (BCG), the live-attenuated form of Mycobacterium bovis. Unfortunately, 60-70% of patients will experience disease recurrence. Our current understanding is that BCG acts within the local bladder tumor microenvironment and draining lymph nodes, leading to the activation of a systemic immune response. Using a murine model of NMIBC, here we investigated whether different routes of BCG administration alter the systemic immune response to BCG and affect tumor size. Methods: To establish syngeneic orthotopic bladder tumors in a mouse model, female C57Bl/6 mice were catheterized and 2.5 x 105 mouse bladder cancer cells (MB49) were instilled into the bladder. Beginning on day 7, mice received either intravesical, intravenous (IV) or intraperitoneal (IP) BCG (8 mg/ml) or saline once weekly for three weeks and bladders were imaged through ultrasound. At endpoint (day 23), tumors, tumor draining lymph nodes (tdLNs), spleen, and bone marrow were harvested and stored. Immune composition of the various lymphoid organs was evaluated using polychromatic flow cytometry. Ex vivo responsiveness to lipopolysaccharide (LPS) was assessed in bone marrow cells by measuring cytokine levels in culture supernatants. Results: Mice treated with IV BCG had significantly smaller tumor volumes when compared to intravesical BCG treatment. Ex vivo LPS stimulation of bone marrow from BCG-treated mice, regardless of administration route, led to increased release of pro-inflammatory cytokines compared with saline controls. IP and IV BCG treatment skewed immune microenvironments of secondary lymphoid organs towards a cytotoxic phenotype compared with intravesical BCG treatment. Within the lymphoid compartment of tdLNs, the proportion of CD8+ T cells was significantly increased while the proportion of CD4+ T cells was significantly decreased in mice treated with IV and IP BCG compared with intravesical BCG. Conversely, the proportion of CD11b+ dendritic cells (DCs) was significantly increased in tdLNs from mice receiving intravesical BCG compared with BCG administered IV or IP. Within the spleen, the proportion of CD8+CD11b- DCs were significantly increased in the DC compartment following IP BCG treatment compared to other treatment routes. Conclusion: This provides evidence that route of BCG administration affects the immune composition of secondary lymphoid organs that may be associated with anti-tumor responses. A better understanding of the mechanism of BCG immunotherapy will lead to novel approaches to optimize anti-tumor immune responses and, consequently, improved patient outcomes. Citation Format: Arielle Grossman, Aline Atallah, Tiziana Cotechini, Jean-Francois Pare, Robert Siemens, Charles H. Graham. Effect of route of Bacillus-Calmette Guerin administration on systemic immune responses in a murine model of non-muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2058.

Introduction: Approximately 80% of bladder cancer patients are initially diagnosed with non-muscle invasive bladder cancer (NMIBC). However, most NMIBC patients have a high recurrence rates, and up to 45% progress to muscle-invasive bladder cancer (MIBC) and metastatic disease. Treatment for NMIBC includes transurethral resection and, depending on the risk of recurrence or progression, intravesical chemotherapy or immunotherapy, such as Bacillus Calmette-Guérin(BCG). Our aim is to use a multigene signature in patients with high-risk NMIBC to determine whether patients may benefit from improved ICIs compared to conventional PD-L1 expression and to evaluate the clinical utility. Methods: A multi-gene signature obtained from the various NMIBC data was applied to stratify the UROMOL2021 cohort (n=535) using consensus clustering. Each subtype was distinguished by biological pathway analysis. Validation analysis was performed in three independent cohorts including the IMvigor210 (n=298), IMvigor010 (n=377) and ABACUS (n=148) clinical trials treated with PD-L1 inhibitors. The log-rank test, chi-square test, Fisher’s exact test, and cox regression analysis were used to evaluate clinical utility. Results: Based on consensus cluster analysis, NMIBC patients in the UROMOL2021 cohort were classified into five subgroups exhibiting unique characteristics, including DNA damage repair (DDR). Cross-validation was performed using two independent NMIBC cohorts and one MIBC cohort. Survival analysis showed that the subgroup associated with DDR (DDR and DDR+Tcell) had the highest rates of relapse and disease progression (progression-free survival, p<0.001) and benefited from Immune checkpoint inhibitors (ICIs) (response, p=0.01; overall survival, p=0.004). Conclusions: This study suggests that the multi-gene signature may play a role to enhance the responsiveness of ICIs for high-risk NMIBC. Additionally, it is important to help improve ICI treatment approaches that currently focus on PD-L1 expression on cancer cells, allowing more patients to receive priority consideration for ICI therapy. Citation Format: Seung-Woo Baek, Seon-Kyu Kim, Sun-Hee Leem, In-Sun Chu. A multigene signature for immunotherapy in patients with high risk non-muscle-invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB091.