Unresponsive Non-muscle Invasive Bladder Cancer Research Articles

N-803 Plus BCG Treatment for BCG-Naïve or -Unresponsive Non-Muscle Invasive Bladder Cancer: A Plain Language Review.

This is a summary of two studies that looked at the safety and effectiveness of a potential new treatment, N-803 (Anktiva), in combination with a standard treatment bacillus Calmette-Guerin (BCG) for people with non-muscle invasive bladder cancer (NMIBC).One study was a Phase 1b study that tested increasing doses of N-803 in combination with the same dose of BCG in people with NMIBC who had never received BCG previously (BCG-naive). The other study is a Phase 2/3 study of N-803 and BCG in people with NMIBC whose cancer wasn't eliminated by BCG alone (BCGunresponsive). In the Phase 1b study, the nine participants were split into three groups of 3 participants who received a dose of 100, 200, or 400μg N-803 along with a standard 50mg dose of BCG. In the Phase 2/3 study, one group (cohort A) of participants with carcinoma in situ (CIS) disease and another group (cohort B) with papillary disease were treated with 400μg N-803 plus 50mg BCG. There was also a cohort C that received only 400μg N-803. Treatments were delivered directly into the bladder once a week for 6weeks in a row. N-803 plus BCG eliminated NMIBC in all nine BCG-naive participants and the effects were long-lasting, with participants remaining NMIBC-free for a range of 8.3 to 9.2years.As reported in 2022, cancer was eliminated in 58 of 82 (71%) participants with BCG-unresponsive CIS disease and the effect was also long-lasting. Importantly, approximately 90% of the successfully treated participants avoided surgical removal of the bladder. In cohort B participants with papillary disease, 40 of 72 (55.4%) were cancer-free 12months after treatment. N-803 used alone was only effective in 2 of 10 participants. In both studies, the combination of N-803 and BCG was found to be associated with very few adverse events.Based on results from the Phase 2/3 study, the U.S. Food and Drug Association (FDA) approved the use of N-803 plus BCG for the treatment of BCG-unresponsive bladder CIS with or without Ta/T1 papillary disease.Clinical Trial Registration: NCT02138734 (Phase 1b study), NCT03022825 (Phase 2/3 study).

Letter: Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin–Unresponsive Nonmuscle Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial

Letter: Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin–Unresponsive Nonmuscle Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial

Relevance of immune tumor microenvironment and its interaction with HABP4 and SERBP1 proteins in bladder cancer.

e15187 Background: This study characterized and compared the immunohistochemical signatures associated with the cytotoxic inflammatory response (IFN-γ, CX3CR1+CD8+ T cells, iNOS+ M1 macrophages), immune checkpoints (PD-L1, CTLA-4), and the presence of immunosuppressive cells (CD163+M2 macrophages, Foxp3+regulatory T (Treg) cells) within bladder cancer samples. Furthermore, it aimed to correlate these immune signatures with the functional dynamics of Hyaluronic Acid Binding Protein 4 (HABP4) and Serpin mRNA Binding Protein 1 (SERBP1), proposing a novel perspective on the immunobiology of bladder cancer and its implications for targeted therapeutic strategies. Methods: A total of 30 formalin-fixed, paraffin-embedded bladder samples were obtained from patients aged 34 to 96 years (average 65 years) diagnosed with bladder cancer at the Municipal Hospital of Paulínia, Brazil. The samples were divided into three groups (n = 10 samples per group): Group 1 - Initial Non-Muscle Invasive Bladder Cancer (NMIBC); Group 2 - Bacillus Calmette-Guerin (BCG)-unresponsive NMIBC; and Group 3 - Muscle Invasive Bladder Cancer. Subsequently, the samples were submitted to immunohistochemical analyses. The retrospective anonymous study was approved by the local ethics committee (Clinical Trial: RBR-6swqd2). Results: Our results demonstrated that total immunoreactivities for IFN-γ, iNOS and CX3CR1 were significantly higher (p < 0.01) in Group 1 compared to Groups 2 and 3. CTLA-4 and PD-L1 immunoreactivities were significantly higher (p < 0.01) in Group 1 compared to Groups 2 and 3. Conversely, immunoreactivities for CD163 and Foxp3 were significantly higher (p < 0.01) in Groups 2 and 3 compared to Group 1. This study marks the first elucidation of HABP4 and SERBP1 immunoreactivities in the context of bladder cancer. We observed that immunoreactivity for SERBP1 was significantly higher (p < 0.01) in Groups 2 and 3 than in Group 1, implicating its overexpression in the facilitation of tumor progression. In a contrasting manner, HABP4 demonstrated significantly greater immunoreactivity (p < 0.01) in Group 1 compared to Groups 2 and 3, indicating a potential inhibitory effect on cellular proliferation. Conclusions: The augmented presence of Foxp3+Treg cells and CD163+M2 macrophages, concomitant with SERBP1 overexpression and the decrease of immune checkpoints, likely compromises the therapeutic efficacy of BCG. This immunosuppressive milieu hinders the activation, proliferation, and effector functions of CD8+ T cells, thereby promoting tumor progression. Conversely, a heightened infiltration of CX3CR1+CD8+ T cells and iNOS+M1 macrophages promotes a cytotoxic microenvironment, rendering it more amenable to immunotherapeutic interventions.

NCCN Guidelines® Insights: Bladder Cancer, Version 3.2024.

Bladder cancer, the sixth most common cancer in the United States, is most commonly of the urothelial carcinoma histologic subtype. The clinical spectrum of bladder cancer is divided into 3 categories that differ in prognosis, management, and therapeutic aims: (1) non-muscle-invasive bladder cancer (NMIBC); (2) muscle invasive, nonmetastatic disease; and (3) metastatic bladder cancer. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Bladder Cancer, including changes in the fifth edition of the WHO Classification of Tumours: Urinary and Male Genital Tumours and how the NCCN Guidelines aligned with these updates; new and emerging treatment options for bacillus Calmette-Guérin (BCG)-unresponsive NMIBC; and updates to systemic therapy recommendations for advanced or metastatic disease.

Correction to: Nadofaragene firadenovec in high-risk Bacillus Calmette Guérin unresponsive non-muscle invasive bladder cancer: a profile of its use

Correction to: Nadofaragene firadenovec in high-risk Bacillus Calmette Guérin unresponsive non-muscle invasive bladder cancer: a profile of its use

Disease progression in Bacillus Calmètte Guerin unresponsive non-muscle invasive bladder cancer patients with carcinoma in situ, participating in clinical trials on bladder-sparing treatment.

Disease progression in Bacillus Calmètte Guerin unresponsive non-muscle invasive bladder cancer patients with carcinoma in situ, participating in clinical trials on bladder-sparing treatment.

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

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

Cost-effectiveness-analysis of different treatment modalities in bacillus Calmette-Guérin (BCG) unresponsive non-muscle invasive bladder cancer (NIMBC).

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%.

BladderGATE: Atezolizumab + intravesical BCG (bacillus Calmette-Guerin) upfront combination in patients with high risk non-muscle invasive bladder cancer (NMIBC)—Phase I-II ONCOSUR study.

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 .

Bladder sparing by short-course radiotherapy combined with toripalimab in high-risk/extremely high-risk non-muscle invasive bladder cancer (HOPE-04): study protocol for a single-arm, prospective, phase II trial

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...

Controversies in terminology associated with management of BCG-unresponsive NMIBC in Asia-Pacific.

Examine the understanding of terminologies and management patterns of bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle invasive bladder cancer (NMIBC) in six territories in Asia-Pacific. This study involved two phases: (1) a survey with 32 urologists and 7 medical oncologists (MOs) and (2) a factorial experiment and in-depth interviews with 23 urologists and 2 MOs. All clinicians had ≥8 years' experience managing NMIBC patients in Australia, Hong Kong, Japan, South Korea, Singapore, and Taiwan. Data from Phase 1 were summarized using descriptive statistics; content and thematic analyses applied in Phase 2. In phase 1, 35% of clinicians defined BCG-unresponsive as BCG-refractory, -relapse and -resistant, 6% defined it as BCG-refractory and -relapse; 22% classified BCG-failure as BCG-refractory, -relapse, -resistant, and when muscle-invasive bladder cancer is detected. If eligible and willing, 50% (interquartile range [IQR], 50%-80%) of BCG-unresponsive patients would undergo radical cystectomy (RC), and 50% (IQR 20%-50%) of RC-eligible patients would receive bladder-sparing treatment or surveillance. In phase 2, we found that 32%, 88%, and 48% of clinicians, respectively, used "BCG-unresponsive," "BCG-refractory," and "BCG-relapse" in clinical practice but with no consistent interpretation of the terms. Compared with EAU definitions, 8%-60% of clinicians appropriately classified 9 tumor types that are persistent or recurrent after adequate BCG. Fifty percent of clinicians mentioned a lack of bladder-preserving treatment that outperforms RC in quality of life as a reason to retreat BCG-unresponsive patients with BCG. Our study revealed varied understanding and application of BCG-unresponsive terminologies in practice. There is a need for a uniform and simple definition of BCG-unresponsive disease in Asia-Pacific.

Nadofaragene firadenovec: a breakthrough in the field of bladder oncology

Muscle-invasive bladder tumors pose a grave mortality risk due to their propensity for distant metastases. The therapeutic spectrum for such tumors encompasses surgery, chemotherapy, and radiation, tailored to the cancer’s severity. In the context of high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC), a novel treatment has emerged as a beacon of hope. Nadofaragene firadenovec, a pioneering gene therapy, has gained worldwide approval for combating this condition, marking a watershed moment in bladder cancer therapy. Nadofaragene firadenovec is ingeniously designed to address high-risk BCG-unresponsive NMIBC, particularly carcinoma in situ (CIS) with or without papillary tumors, in adult patients. Rooted in a vector DNA, this therapy encodes interferon (IFN)-2b, which imparts urothelial cells with the ability to generate IFN-2b. The resulting cascade of events triggers a multifaceted assault on cancer, characterized by its immunostimulatory, antiangiogenic, and apoptotic effects. The therapeutic efficacy of nadofaragene firadenovec rests on its capacity to exploit the transformed urothelial cells to deliver these targeted anticancer activities. The evolutionary trajectory of nadofaragene firadenovec culminated in its monumental approval in December 2022 by the United States, signifying a pivotal juncture in the field. Notably, a segment of patients, approximately 30%, prove refractory to BCG treatment. For these individuals, alternative therapeutic avenues are imperative. Presently, the landscape for patients with non-muscle invasive bladder cancer lacks a definitive, enduring solution. Against this backdrop, the introduction of nadofaragene firadenovec heralds a momentous stride toward the global availability of an authorized therapeutic intervention.

PD13-12 BLADDER SPARING TREATMENT IN PATIENTS WITH BCG UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER: AN ANALYSIS OF LONG-TERM SURVIVAL OUTCOMES

You have accessJournal of UrologyCME1 Apr 2023PD13-12 BLADDER SPARING TREATMENT IN PATIENTS WITH BCG UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER: AN ANALYSIS OF LONG-TERM SURVIVAL OUTCOMES Wei Shen Tan, Valentina Grajales, Roberto Contieri, Patrick Hensley, Kelly Bree, Pavlos Msaouel, Charles Guo, Neema Navai, Colin Dinney, and Ashish Kamat Wei Shen TanWei Shen Tan More articles by this author , Valentina GrajalesValentina Grajales More articles by this author , Roberto ContieriRoberto Contieri More articles by this author , Patrick HensleyPatrick Hensley More articles by this author , Kelly BreeKelly Bree More articles by this author , Pavlos MsaouelPavlos Msaouel More articles by this author , Charles GuoCharles Guo More articles by this author , Neema NavaiNeema Navai More articles by this author , Colin DinneyColin Dinney More articles by this author , and Ashish KamatAshish Kamat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003260.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In recent years, more patients are selecting to forgo radical cystectomy (RC) and select bladder sparing treatment (BST) for Bacillus Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC). Herein, we assessed long-term survival outcomes of BCG unresponsive NMIBC patients treated with BST versus early RC. METHODS: We performed an IRB approved retrospective study analyzing patients with BCG unresponsive NMIBC diagnosed between April 2001 and September 2021 at our institution. Survival outcomes between the following patient cohorts were compared: 1) Early RC versus BST and 2) Early RC versus delayed RC. Primary endpoint was overall-(OS) and cancer-specific survival (CSS). Cox-regression was used to estimate OS, CSS, high-grade recurrence-free survival (RFS) and progression-free survival (PFS) endpoints. RESULTS: A total 118 patients who met criteria for BCG unresponsive disease were identified (80 BST versus 38 early RC). Patients undergoing early RC were more likely to have higher T1 stage (52.6% vs 35.0%, p=0.048) and lymphovascular invasion (10.5% vs 0%, p=0.003) compared to those treated with BST. Comparative outcomes for OS (HR: 1.34, 95% CI: 0.65-2.76, log-rank p=0.429) and CSS (HR: 0.84, 95% CI: 0.21-3.38, log-rank p=0.803) between early RC and BST were not significant (inconclusive). With a median follow-up of 72.1 months (IQR: 30.1-134.0), at 60 months, BST treated patients had a high-grade RFS rate of: 37%, PFS to muscle-invasive disease/metastasis rate: 84% and avoidance of RC rate: 81%. The risk of high-grade recurrence was higher in current smokers (HR: 6.00, 95% CI: 1.73-20.6, p=0.005). For patients undergoing RC for BCG unresponsive disease, median time to RC were 2.1 months and 15.8 months for early and delayed RC respectively. Comparative outcomes were similar for the early and delayed RC: OS (58% vs 54%) (HR: 1.17, 95% CI: 0.50-2.71, p=0.717) and CSS (81% vs 81%) (HR: 1.07, 95% CI: 0.23-4.92, log-rank p=0.927). CONCLUSIONS: Long-term survival outcomes following BST (with delayed RC when indicated) in patients with BCG unresponsive NMIBC is not inferior compared to early RC. Source of Funding: This research was supported by the Wayne B. Duddlesten Professorship in Cancer Research, the Raymond and Maria Floyd Bladder Cancer Research Foundation Grant, NIH/NCI UTMD Anderson SPORE in Genitourinary Cancer (P50CA091846) and the Cancer Center Support Grant (NCI Grant P30 CA016672) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e410 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Wei Shen Tan More articles by this author Valentina Grajales More articles by this author Roberto Contieri More articles by this author Patrick Hensley More articles by this author Kelly Bree More articles by this author Pavlos Msaouel More articles by this author Charles Guo More articles by this author Neema Navai More articles by this author Colin Dinney More articles by this author Ashish Kamat More articles by this author Expand All Advertisement PDF downloadLoading ...

In Brief: Adstiladrin – A Gene Therapy for Bladder Cancer

Nadofaragene firadenovec-vncg (Adstiladrin – Ferring), an adenoviral vector-based gene therapy, has been approved by the FDA for treatment of adults with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors. It is the first adenoviral vector-based gene therapy to be approved in the US for this indication. The immune checkpoint inhibitor pembrolizumab (Keytruda) was approved for the same indication in 2021.

Nadofaragene Firadenovec: First Approval.

Nadofaragene firadenovec (nadofaragene firadenovec-vncg; Adstiladrin®) is a non-replicating adenoviral vector-based gene therapy developed by Ferring Pharmaceuticals for the treatment of high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC). Nadofaragene firadenovec constitutes vector DNA that encodes for interferon (IFN)-α2b and is the first approved gene therapy in bladder cancer. The production of IFN-α2b by transfected urothelial cells is associated with anticancer activity, including immunostimulatory, antiangiogenic and apoptotic effects. In December 2022, nadofaragene firadenovec received its first global approval in the USA for the treatment of high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumours in adults. This article summarizes the milestones in the development of nadofaragene firadenovec leading to this first approval for this indication.

Intravesical gemcitabine and docetaxel in the treatment of BCG-naïve non–muscle invasive urothelial carcinoma of the bladder: Updates from a phase 2 trial.

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]

Elicitation of Health State Utilities Associated with Progression from Bacillus Calmette-Guerin (BCG) Unresponsive Non-muscle Invasive Bladder Cancer (NMIBC).

The treatments for high-grade non-muscle invasive bladder cancer (NMIBC) vary between bladder preserving intravesical approaches and radical cystectomy. The impact of these treatments on health-related quality of life may vary widely. The purpose of this study was to elicit the general public's perspective on quality of life, measured as utility scores associated with treatment for Bacillus Calmette-Guerin (BCG)-unresponsive NMIBC and disease progression, for supporting economic evaluation of newly developed treatments for NMIBC. Part I involved the development and testing of health states describing NMIBC, which was informed by a rapid review, expert input and a patient advisor. Part II involved elicitation of societal utility values for the different health states. Time trade-off (TTO) interviews were conducted with members of the UK general public. Five health states described different NMIBC scenarios including disease recurrence and progression. Participants ranked each health state, followed by the TTO valuation exercise. Descriptors included NMIBC symptom severity, impact and treatment characteristics. In total, 202 members of the general public participated. The mean age was 46 (standard deviation [SD] 14.6) years. Sample mean (SD) EQ-5D-5L visual analogue scale (VAS) and index scores were 83.2 (12.3) and 0.89 (0.18), respectively. Mean utilities were 0.781 for No High-Grade Recurrence, 0.586 for High-Grade Recurrence, 0.572 for >1-Year Post-cystectomy and 0.283 for metastatic disease. The First Year Post-cystectomy path health state had a mean utility of 0.288. Pairwise comparisons found statistically significant differences between utilities (p < 0.001), except between High-Grade Recurrence and > 1-Year Post-cystectomy (p = 0.524). There were significant differences in utility scores by age and employment status. This study provides utility scores for health states describing living with NMIBC, which is associated with a significant health-related quality-of-life burden. These values address an existing gap in available data and have the potential to be used in models evaluating the cost-effectiveness of both current and newly developed treatments for bladder cancer.

Outcomes of Patients with Bacillus Calmette-Guérin (BCG)-Unresponsive Non-Muscle Invasive Bladder Cancer as Defined by the U.S. Food and Drug Administration.

Limited data are available on the outcomes of patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to intravesical bacillus Calmette-Guérin (BCG), as defined by the United States Food and Drug Administration. To define the outcomes of patients with BCG-unresponsive NMIBC. This was a retrospective, single-institution observational cohort study. Records of patients managed at our institution for BCG-unresponsive NMIBC between 2005 and 2020 were reviewed and clinical outcomes evaluated. The study included 149 patients. Management was with initial radical cystectomy in 60 patients (40%) and initial bladder-sparing therapy (BST) in 89 patients (60%). Overall survival was greater among patients undergoing RC than BST (HR 1.83, 95% CI 1.04-3.22, p = 0.036), potentially due to patient selection, as no significant difference was noted for metastasis-free or cancer-specific survival. Patients opting for initial BST had high rates of treatment failure, with estimated 5-year cystectomy-free survival of only 42%. Patients who received additional lines of BST after a subsequent failure were at increased risk of having ≥pT3 or pN+ disease at cystectomy (42% for ≥2 lines BST, versus 18% for 1 line BST and 15% for initial cystectomy, p = 0.038). Among patients who underwent initial BST for BCG-unresponsive NMIBC, rates of treatment failure were very high. Patients who underwent delayed cystectomy after ≥2 lines of BST had elevated rates of extravesical disease. Our observations emphasize the importance of recent and ongoing clinical trials in this clinical space.

Treatment and disease management patterns for bacillus Calmette-Guérin unresponsive nonmuscle invasive bladder cancer in North America, Europe and Asia: A real-world data analysis.

BackgroundThis study examined real-world treatment and management of bacillus Calmette-Guérin (BCG)-unresponsive patients across 3 continents, including patients unable or unwilling to undergo cystectomy.Materials and methodsPhysicians actively involved in managing patients with nonmuscle invasive bladder cancer completed online case report forms for their 5 consecutive patients from the broad BCG-unresponsive population and a further 5 consecutive BCG-unresponsive patients who did not undergo cystectomy (in Japan, physicians provided a total of 5 patients across both cohorts).ResultsMost patients had received 1 (37%) or 2 (24%) maintenance courses of BCG. Five or more maintenance BCG courses were received by patients in Japan (59%) and China (31%), while in Germany 76% of patients received only 1 course. Most patients became BCG-unresponsive during their first (44%) or second (22%) treatment course; in Germany, 77% became BCG-unresponsive during their first treatment course. Most countries did not provide another course of BCG after a patient first became unresponsive, whereas unresponsive patients in Japan and China were most likely to be retreated with BCG. “Untreated - on watch and wait” was the main treatment/management approach received post-BCG treatment for 42% or more of patients in most countries except China (39%) and the United States (36%). “Following treatment guidelines” was consistently the top reason for post-BCG treatment selection across all treatment options.ConclusionsThis study confirmed the global unmet need for patients with nonmuscle invasive bladder cancer, and found that many patients experienced periods of no treatment after not responding to BCG therapy.

Crosstalk among T-cell CX3CR1, immune checkpoints and toll-like receptor 4 signaling pathway in BCG-unresponsive nonmuscle invasive bladder cancer: Mechanism of action of OncoTherad Nano-Immunotherapy.

e16551 Background: This study detailed and characterized the mechanisms of action of OncoTherad nano-immunotherapy based on modulation of Toll-like Receptor 4 (TLR4) signaling pathway, CX3C chemokine receptor 1 (CX3CR1, a marker of T-cell differentiation) and immune checkpoints in patients with Bacillus Calmette-Guérin (BCG)-unresponsive high-grade non-muscle invasive bladder cancer. Methods: A single-center open-label (Paulinia Municipal Hospital, Brazil) and single-arm phase 1/2 study (Clinical Trial: RBR-6swqd2) was applied in 44 patients (30 male and 14 female) with BCG-unresponsive NMIBC (≥ 1 prior course of BCG therapy) submitted to OncoTherad immunotherapy for 24 months. Patient follow-ups were performed with systematic mapping biopsies of the bladder every 3 months for the first year and every 6 months thereafter for up to 2 years. Bladder biopsies of each patient (n = 44) were divided into 2 groups: Group 1 (initial biopsy, before OncoTherad treatment); and Group 2 (bladder biopsy after OncoTherad treatment). Subsequently, the samples were submitted to immunohistochemistry analysis: TLR4-mediated IFN-γ production signaling pathway (TRIF, TBK1, IRF-3), CX3CR1+CD8+ T-cells, immune checkpoints (PD-1/PD-L1 CTLA-4) and Regulatory T cells (FOXP3). Results: After 24-months follow-up, pathological complete response rate was 72.7% (95% CI) and recurrence-free survival of 21.4 months. Bladder samples from patients submitted to OncoTherad treatment (Group 2) showed intensified TLR4, TRIF, TBK1, IRF-3 and IFN-γ immunoreactivities when compared (p &lt; 0.01) to initial biopsies (Group 1). Furthermore, as result of interferon signaling pathway (TRIF-dependent pathway) induction by OncoTherad, intensified CX3CR1 immunoreactivities (p &lt; 0.01) were found in the Group 2. In contrast, PD-1/PD-L1 immunoreactivities were decreased (p &lt; 0.01) in the Group 2 when compared to Group 1. No statistical differences were found between the two groups for FOXP3 and CTLA4. Conclusions: OncoTherad nano-immunotherapy led to activation of TLR4-mediated innate immune system, resulting in increased interferon signaling pathway, which was fundamental in the activation of antitumor CD8+ T-cells and decrease of PD-1/PD-L1 expression in the bladder microenvironment. These important findings are relevant concerning the treatment of patients with NMIBC presenting high-risk of progression that are BCG-unresponsive.