BCG-unresponsive Non-muscle Invasive Bladder Cancer Research Articles

HLA-E and NKG2A Mediate Resistance to M. bovis BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Mycobacterium bovis Bacillus Calmette-Guerin (BCG) is the primary treatment for non-muscle-invasive bladder cancer (NMIBC), known to stimulate inflammatory cytokines, notably interferon (IFN)-γ. We observed that prolonged IFN-γ exposure fosters adaptive resistance in recurrent tumors, aiding immune evasion and tumor proliferation. We identify HLA-E and NKG2A, part of a novel NK and T cell checkpoint pathway, as key mediators of resistance in BCG-unresponsive NMIBC. IFN-γ enhances HLA-E and PD-L1 expression in recurrent tumors, with an enrichment of intra-tumoral NKG2A-expressing NK and CD8 T cells. CXCL9 + macrophages and dendritic cells and CXCL12-expressing stromal cells likely recruit CXCR3/CXCR4-expressing NK and T cells and CXCR7 + HLA-E HIGH tumor cells. NK and CD8 T cells remain functional within BCG-unresponsive tumors but are inhibited by HLA-E and PD-L1, providing a framework for combined NKG2A and PD-L1 blockade strategy for bladder-sparing treatment of BCG-unresponsive NMIBC.

2023TiP A phase I/II study of EG-70 (detalimogene voraplasmid) intravesical monotherapy for patients (pts) with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS)

2023TiP A phase I/II study of EG-70 (detalimogene voraplasmid) intravesical monotherapy for patients (pts) with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS)

Recent Advances in Drug Delivery Strategies for High-Risk BCG-Unresponsive Non-Muscle Invasive Bladder Cancer: A Brief Review from 2018 to 2024.

High-risk BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) is a condition that is typically treated with Bacillus Calmette-Guérin (BCG) therapy. Unfortunately, NMIBC is characterized by high recurrence, with a significant percentage of BCG patients ultimately requiring radical cystectomy. As a consequence, the development of effective new therapies to avoid RC has become a rapidly evolving field to address this unmet clinical need. To date, three biologics-Keytruda, Adstiladrin, and Anktiva-have been approved by the FDA, and multiple drug modalities, particularly gene therapies, have shown promising results in clinical trials. Advances in drug delivery strategies, such as targeted delivery, sustained release, and permeabilization of protective layers, are critical in overcoming the challenges posed by therapeutic intervention in bladder cancer. This review focuses on high-risk BCG-unresponsive NMIBC therapies that have been or are currently being investigated in clinical trials, offering a broad overview of the delivery system designs and up-to-date clinical outcomes that have been reported as of July 2024. It aims to inform the development of future drug delivery systems for second-line therapies in high-risk BCG-unresponsive NMIBC.

Long-term outcomes of bladder-sparing therapy vs radical cystectomy in BCG-unresponsive non-muscle-invasive bladder cancer.

To quantify the oncological risks of bladder-sparing therapy (BST) in patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) compared to upfront radical cystectomy (RC). Pre-specified data elements were collected from retrospective cohorts of patients with BCG-unresponsive NMIBC from 10 international sites. After Institutional Review Board approval, patients were included if they had BCG-unresponsive NMIBC meeting United States Food and Drug Administration criteria. Oncological outcomes were collected following upfront RC or BST. BST regimens included re-resection or surveillance only, repeat BCG, intravesical chemotherapy, systemic immunotherapy, and clinical trials. Among 578 patients, 28% underwent upfront RC and 72% received BST. The median (interquartile range) follow-up was 50 (20-69) months. There were no statistically significant differences in metastasis-free survival, cancer-specific survival, or overall survival between treatment groups. In the BST group, high-grade recurrence rates were 37% and 52% at 12 and 24 months and progression to MIBC was observed in 7% and 13% at 12 and 24 months, respectively. RC was performed in 31.7% in the BST group and nodal disease was found in 13% compared with 4% in upfront RC (P = 0.030). In a selected cohort of patients, initial BST offers comparable survival outcomes to upfront RC in the intermediate term. Rates of recurrence and progression increase over time especially in patients treated with additional lines of BST.

New therapeutic approaches for non-muscle invasive bladder cancer-is organ preservation also possible after BCG (Bacillus Calmette Guérin)?

Bacillus Calmette-Guérin (BCG) therapy is the standard of care in the treatment of high-risk non-muscle invasive bladder cancer (NMIBC). In the absence of aresponse to BCG and persistent high-grade disease, cystectomy is recommended depending on the clinical risk. Avariety of targeted therapy approaches, which aim at immune- and gene-based molecular targets, such as PD-(L)1 and FGFR, are currently being investigated in randomized studies for BCG-unresponsive NMIBC. Furthermore, novel forms of application for instillation therapy, such as the TAR device, in combination with gemcitabine or erdafitinib are being investigated in clinical trials in order to extend the duration of action of the active substance on the urothelium. Thus, there are now many developments that could make bladder-preserving therapy with comparable survival data possible as an alternative to BCG or in the event of BCG failure. In the future, it will be necessary to clarify how BCG response can be predicted by using molecular markers and how to define risk groups that should primarily be given an alternative therapy to BCG.

Does radical cystectomy still have a role in BCG-unresponsive nonmuscle invasive bladder cancer?

Several novel therapies approved by the Food and Drug Administration (FDA) and explosion of clinical trials have changed the landscape Bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle invasive bladder cancer (NMIBC). Given the recent advancements in bladder sparing options, the role of radical cystectomy (RC) in BCG-unresponsive NMIBC remains a subject of debate. All three novel agents currently approved by the FDA for BCG-unresponsive NMIBC have strict indication [carcinoma in situ (CIS)], low response rate, and short response duration. Some promising new agents are awaiting results and/or FDA approval. RC still provides the best oncologic control and acceptable quality of life, and potentially represents the most cost-effective option. It is an exciting time for the urologic oncology community to see the FDA approvals of some of the novel bladder sparing therapies and expansion of ongoing clinical trials. Yet, RC should still be considered as the gold standard of BCG-unresponsive NMIBC. We also must be cautious and selective in recommending bladder sparing options for patients with BCG-unresponsive NMIBC.

Nogapendekin alfa Inbakicept: First Approval.

Nogapendekin alfa inbakicept (ANKTIVA®; nogapendekin alfa inbakicept-pmln) is a recombinant interleukin-15 (IL-15) superagonist protein complex being developed by Altor BioScience, LLC, an indirect wholly owned subsidiary of ImmunityBio, Inc., for the treatment of solid and haematological cancers and HIV infection. In April 2024, nogapendekin alfa inbakicept was approved for use with Bacillus Calmette-Guérin (BCG) for the treatment of adult patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumours in the USA. This article summarizes the milestones in the development of nogapendekin alfa inbakicept leading to this first approval for the treatment of cancer.

In brief: Anktiva for bladder cancer.

Nogapendekin alfa inbakicept-pmln (Anktiva – ImmunityBio), a first-in-class interleukin-15 (IL15) receptor agonist, has been approved by the FDA for use with Bacillus Calmette-Guérin (BCG) for treatment of patients with BCG-unresponsive nonmuscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors.

Cost effectiveness analysis of nadofaragene firadenovec for the treatment of high-risk, bacillus Calmette-Guerin–unresponsive, non-muscle invasive bladder cancer from a US third-party payer perspective.

4598 Retraction The abstract by Yang et al entitled, “Cost effectiveness analysis of nadofaragene firadenovec for the treatment of high-risk, bacillus Calmette-Guerin–unresponsive, non-muscle invasive bladder cancer from a US third-party payer perspective,” ( Journal of Clinical Oncology 42, no. 16_suppl 4598; DOI 10.1200/JCO.2024.42.16_suppl.4598) published on May 29, 2024, has been retracted. The authors wish to retract this article as it is undergoing additional review and further updates are expected. They could not rule out that the current results may be incorrect, inaccurate, or misleading. It is important to provide the best estimate of nadofaragene’s cost effectiveness vs pembrolizumab in this space for healthcare decision making whereas uncertainty remains at this time. The authors are no longer able to endorse the work. This abstract was retracted on August 26, 2024. Background: Bladder cancer is the second most common cancer in the urinary tract in the United States (US), with 75% restricted to the superficial layers of the bladder and termed as non-muscle invasive bladder cancer (NMIBC). Bacillus Calmette-Guerin (BCG) is the standard of care for high risk NMIBC patients; however, bladder preserving treatments are limited after BCG failure. Nadofaragene firadenovec, an interferon-alfa-2b encoding gene therapy, is approved for the treatment of high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumors (CIS ± Ta/T1). This study assessed cost-effectiveness of nadofaragene firadenovec compared to pembrolizumab from a US third-party payer perspective. Methods: A Markov model was developed to estimate total costs, quality-adjusted life-years (QALYs), and corresponding incremental cost per QALY ratios (ICER) over a lifetime time horizon for patients treated with nadofaragene firadenovec or pembrolizumab. In the absence of head-to-head data comparing nadofaragene firadenovec to pembrolizumab, the model population was based on Phase 3 trial for nadofaragene firadenovec (NCT02773849, data cut: July 8, 2019) and included adult patients (mean age of 71.0 years; 11.7% female) with high-risk, BCG unresponsive NMIBC with CIS ± Ta/T1. Pembrolizumab data was informed by the published KeyNote-057 trial (NCT02625961, data-cut: May 25, 2020). The model consisted of 7 mutually exclusive health states with a three-month model cycle: NMIBC disease-free, NMIBC recurrence, MIBC, metastatic disease, cystectomy, post-cystectomy, and death. Drug costs, adverse events (AEs) costs, and health state associated medical costs were included and discounted at 3% annually. The nadofaragene firadenovec and pembrolizumab prices were informed by 2023 U.S. pricing compendia. Sensitivity analyses were performed. Results: Compared to pembrolizumab, nadofaragene firadenovec resulted in an ICER of $123,725 per QALY gained. The incremental cost was $24,194 (nadofaragene firadenovec: $374,280; pembrolizumab: $350,086) and the incremental QALYs were 0.196 (nadofaragene firadenovec: 4.560; pembrolizumab: 4.364). The cumulative drug acquisition and administration costs for nadofaragene firadenovec and pembrolizumab were $181,134 and $141,954 respectively, and AE costs were $248 and $2,749 and medical costs associated with health states were $192,898 and $205,382, respectively. The ICERs for nadofaragene firadenovec remained cost-effective across a majority of the sensitivity analyses and simulations. Conclusions: The analysis suggests that nadofaragene firadenovec is cost-effective compared to pembrolizumab for the treatment of high-risk, BCG unresponsive NMIBC with CIS ± Ta/T1 at a willingness to pay of $150,000/QALY.

A phase 1/2 study of EG-70 (detalimogene voraplasmid) intravesical monotherapy for patients with BCG-unresponsive non-muscle invasive bladder cancer with carcinoma in situ.

TPS4626 Background: High-risk non-muscle-invasive bladder cancer (NMIBC) is treated with adjuvant intravesical Bacille Calmette-Guérin (BCG). However, approximately 50% of patients experience recurrence and/or progression after BCG treatment and are considered unresponsive. EG-70 (detalimogene voraplasmid) is an investigational drug product that was specifically engineered for intravesical administration to elicit local stimulation of anti-tumor immune responses in the bladder and drive durable efficacy in patients with BCG-unresponsive NMIBC, while mitigating the risk of systemic toxicities from immune stimulation. The phase 1 (dose-escalation) part of the first-in-human LEGEND (NCT04752722) phase 1/2, open-label, multicenter study of EG-70 in patients with high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) is complete: intravesical instillation of EG-70 was well tolerated with an overall complete response (CR) rate of 73%; and the recommended phase 2 dose (RP2D) was identified. Here we describe the ongoing phase 2 part of the study, which opened to enrollment in May 2023. Methods: Patient eligibility criteria: age ≥18 years; ECOG PS 0−2; BCG-unresponsive NMIBC with CIS, with or without resected coexisting papillary tumors, ineligible for, or have elected not to undergo, cystectomy; satisfactory bladder function with ability to retain study drug for ≥60 minutes. Prior checkpoint inhibitor treatment is allowed if completed within 30 days before study entry. Patients are treated with EG-70 at the RP2D (800 µg in 50 mL) by intravesical administration on weeks 1, 2, 5, and 6 of a 12-week cycle, for 4 cycles in one of two cohorts: BCG-unresponsive (Cohort 1); BCG-naïve or BCG-incompletely treated (Cohort 2). Patients in either cohort who exhibit stable disease (SD) or CR at week 12 will continue treatment until week 24; patients with progressive disease (PD) will discontinue treatment. Patients who experience or maintain CR at week 24 will receive additional cycles every 12 weeks until week 48; patients with SD or PD at week 24 will discontinue treatment. Patients with PD at any time after week 24 will discontinue treatment. Phase 2 primary objective: evaluate efficacy (CR rate at week 48) and safety of EG-70. Secondary objectives: evaluate progression-free survival, CR rate at 12, 24, 36 and 48 weeks, and duration of response. The study is being conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and with the principles of the Declaration of Helsinki. All patients provide written informed consent. The ongoing, registration-enabling phase 2 portion of the LEGEND study is anticipated to recruit approximately 100 patients from sites in North America, Europe, and the Asia-Pacific region. Clinical trial information: NCT04752722 .

Antitumor mechanisms of OncoTherad (MRB-CFI-1) nanoimmunotherapy involving monoamine oxidases: Clinical implications in BCG-unresponsive non-muscle invasive bladder cancer.

e14597 Background: Bacillus Calmette-Guérin (BCG) immunotherapy has been the gold standard treatment for non-muscle invasive bladder cancer (NMIBC) for nearly half a century. However, many high-risk patients experience recurrence, including those who progress and eventually become unresponsive to BCG. The emergence of new immunotherapeutic agents has revolutionized the treatment of various tumor types, including urothelial carcinoma. In this context, our research group has developed OncoTherad (MRB-CFI-1) immunotherapy, which has shown promising results in cancer treatment, particularly in NMIBC. Given the inherent complexity of the immune response, patient selection and the development of biomarkers to guide the identification of individuals who will derive the greatest benefit from a specific immunotherapy remain crucial. Over the past years, several studies have demonstrated the upregulation of monoamine oxidases (MAOs) in tumor progression and metastasis. Therefore, the objectives of this present study were to characterize the effects of OncoTherad (MRB-CFI-1) on the modulation of MAOs (MAO-A and MAO-B) in the bladder of patients with BCG-unresponsive NMIBC. Methods: A total of 40 bladder biopsies from patients with BCG-unresponsive NMIBC treated with OncoTherad (MRB-CFI-1) were collected and analyzed from Paulínia Municipal Hospital (HMP). These samples were then divided into two groups (n=20 per group): Group 1 (biopsy before OncoTherad treatment) and Group 2 (biopsy after OncoTherad treatment). Subsequently, the samples underwent immunohistochemical analyses for MAO-A and MAO-B. The retrospective anonymous study was approved by the local ethics committee (Clinical Trial: RBR-6swqd2). Results: Our results demonstrated high immunoreactivities for both MAO-A and MAO-B in the bladder tumor microenvironment prior to OncoTherad (MRB-CFI-1) treatment, confirming that the pattern reported in literature studies can also be observed in NMIBC. Total immunoreactivities for MAO-A did not differ statistically between bladder biopsies of Groups 1 and 2, indicating that this treatment does not interfere with the action of MAO-A in bladder tissue. In contrast, immunoreactivities for MAO-B were significantly lower (p<0.05) in the Group 2 when compared to Group 1 suggesting that this immunotherapy reversed the immunosuppressive state and tumor progression induced by MAO-B. Conclusions: Taken together, our results support the use of MAO-B as a biomarker for clinical response to OncoTherad (MRB-CFI-1) immunotherapy.

Abstract PR006: EG-70 (detalimogene voraplasmid), a novel, non-viral intravesical gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: Preclinical characterization and translation into the clinic

Abstract Background: EG-70 (detalimogene voraplasmid) is a novel, investigational, non-integrating, non-viral gene therapy specifically engineered to elicit local stimulation of anti-tumor immune response in the bladder and to drive durable efficacy in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer (NMIBC), while mitigating the risk of systemic toxicities from immune stimulation. Previous preclinical data indicate that intravesical instillation (IVI) of EG-70 results in local expression of transgene products in murine and non-human primate models. Here we describe the latest preclinical data to support the mechanism of action of EG-70 and Phase 1 clinical study results for EG-70 in the treatment of BCG-unresponsive NMIBC. Methods: Preclinical: A murine surrogate formulation of EG-70 (mEG-70) was administered locally to the bladder by IVI in C57BL/6 mice. Efficacy was assessed in a luciferase-expressing MB49 model of orthotopic bladder cancer. Following confirmation of cancer cell implantation by in vivo imaging, mice received two weekly IVIs of mEG-70. Immune profiling was evaluated by assessing protein expression levels and cell compositions (via MSD, flow cytometry, and immunohistochemistry). Immune cell depletion studies were conducted using specific antibodies directed against CD4 or CD8 antigen to assess T-cell contribution to efficacy. Clinical: In a Phase 1/2 study in high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) (LEGEND; NCT04752722), EG-70 was assessed in four separate dose groups. Results: Preclinical: In a mouse model of orthotopic bladder cancer, IVI of mEG-70 caused striking remodeling of the tumor microenvironment from an immunosuppressive phenotype to a pro-inflammatory milieu supportive of tumor clearance. This was demonstrated by a significant decrease in myeloid cells and IL-4 cytokine levels, an increase in NK-cells and T-cells, and an increase in pro-inflammatory cytokines in tumor tissue. Accordingly, administration of mEG-70 was associated with marked reduction in tumor burden and significant improvement of survival. The anti-tumor response was largely immune-mediated as demonstrated by the critical role of T-cells, durable clearance of tumors, and protection against subsequent tumorigenic re-challenge, both locally in the bladder as well as distally, after flank implantation. Clinical: Results from the Phase 1 portion of the LEGEND study show that IVI of EG-70 was well-tolerated in patients with high-risk BCG-unresponsive NMIBC with CIS across all dose levels, with an overall complete response rate of 73%. Conclusions: The latest preclinical findings demonstrate that EG-70 has the potential to deliver immunostimulatory payloads locally to the bladder. The mechanism of action described preclinically has been translated into the clinic, in the Phase 1 portion of the LEGEND study in patients with BCG-unresponsive NMIBC with CIS. Citation Format: Marie-Line Goulet, Shauna M Dauphinee, Daniel Veilleux, Kristine S Louis, David Lazure, Sarah Stevenson, Darius Bilimoria, Fazmina Zamzameer, Ximin Chen, Sébastien Sublemontier, Sahar Amirkhani, Carlos Fleet, Richard Bryce, Matthew Bui, Shreyas Joshi, Susan J. Kalota, Anthony Cheung, James Sullivan. EG-70 (detalimogene voraplasmid), a novel, non-viral intravesical gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: Preclinical characterization and translation into the clinic [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 PR006.

Abstract IA012: Novel approaches to the management of non-muscle invasive bladder cancer

Abstract Non-muscle invasive bladder cancer (NMIBC) is a prevalent disease with a high recurrence rate and the potential to progress to muscle-invasive stages. While transurethral resection and bacillus Calmette-Guerin (BCG) immunotherapy remain the mainstay of treatment, limitations exist, particularly for high-grade and BCG-unresponsive NMIBC. This necessitates the exploration of novel therapeutic strategies. This talk will explore promising avenues in NMIBC management, including combination intravesical therapies, enhanced delivery methods for existing treatments, and emerging fields like gene therapy, targeted therapy, immunotherapy variants, and photodynamic therapy. These approaches hold the potential to improve bladder preservation rates, reduce recurrence, and ultimately enhance patient outcomes across the entire spectrum of NMIBC disease. Citation Format: Ashish M. Kamat. Novel approaches to the management of 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 IA012.

Abstract B019: Identification of gene signatures predictive of response to Ad-IFNα/Syn3 in bladder cancer

Abstract Introduction: Interferon α gene therapy (Ad-IFNα/Syn3) is FDA approved for treatment of BCG-unresponsive non-muscle invasive bladder cancer. Ad-IFNα/Syn3 is a non-replicating adenovirus that when transduced into target tissues, produces IFNa2b protein with anti-tumor activity. In the phase 3 multicenter trial, 45.5% of patients with carcinoma-in-situ and 60% of those with Ta/T1 disease who had a complete response to Ad-IFNα/Syn3 at 3 months remained recurrence free at 12 months. Targeting mechanisms of resistance and identifying predictive biomarkers to improve patient selection and overall response rates is a top priority. Towards this, we treated 29 human bladder cancer cell lines with Ad-IFNα/Syn3 and assessed their responses to therapy. We identified sensitive and resistant cell lines and gene signatures predictive of response. Methods: Human bladder cancer cell lines were grown in MEM supplemented with 10% FBS in 96-well plate. After overnight attachment, these were treated with Ad-IFNα/Syn3 (MOI 1000) and cell titre glow assay was performed 72h post-treatment. Cells were also seeded in 6-well plates. and after 24h cell-free supernatants were collected for ELISA and cells were collected for RNA isolation using RNAqueous Total RNA Isolation kit (Thermo Fisher). RNA quality was assessed using Tapestation. RNAseq analysis was carried out using Ion proton Sequencer. Ingenuity pathway analysis (IPA) and gene set enrichment were performed on the sequencing data for the cell lines. ELISA was used to measure IFNα and IL6 protein levels in cell free supernatants. We also tested organoids developed from bladder cancer patients to test drug efficacy and identify gene signatures. Results: Out of the 29 cell lines, we identified that sensitivity to Ad-IFNα/Syn3 was pronounced in luminal cells (8/13 luminal cell lines). Most basal cells were either resistant (>70% viability) or only moderately sensitive to Ad-IFNα/Syn3 (between 70-40% viability) when compared to control. We selected 7 cell lines for sequencing and ELISA measurements: luminal cell lines BV, UC6, Rt4V6 and UC5, and basal cell lines ScaBER, HT1197, and T24. All cell lines mentioned above could be successfully transduced by the adenoviral vector as measured by increased expression of IFNα protein in the cell-free supernatants. Ad-IFNα/Syn3-sensitive luminal cell lines at baseline had lower IFNα and IFNγ scores when compared to resistant basal cell lines. We identified several cell-death pathways enriched in treated cells that were sensitive to Ad-IFNα/Syn3. IL6 measurements in cell free supernatants revealed increased expression of IL6 after treatment in sensitive cells. However, in resistant cells IL6 expression was either high at baseline (ScaBER) or both undetectable at baseline and after treatment (UC5). Conclusion: Our results suggest that the luminal cell lines are more sensitive to Ad-IFNα/Syn3 and that high baseline expression of IFNα and IFNγ in basal cell lines contributes to resistance. IL6 levels are also predictive of response to Ad-IFNα/Syn3. Citation Format: Morgan E. Pierce, Alexis R. Steinmetz, Aruna Nannapaneni, Tanner S. Miest, David J. McConkey, Sharada Mokkapati, Colin P.N. Dinney. Identification of gene signatures predictive of response to Ad-IFNα/Syn3 in 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 B019.

Abstract CT086: Phase I study of intravesical Fc-optimized anti-CD40 agonist antibody 2141-V11 for non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG) therapy

Abstract Introduction: The CD40-CD40L pathway is crucial for activating antigen-presenting cells and initiating tumor-specific T cell responses across various malignancies. However, prior agonistic anti-CD40 antibodies have encountered limited clinical success and significant toxicity. Our previous studies demonstrate that interactions between the antibody Fc domain and the inhibitory Fc-gamma receptor FcγRIIB are critical for efficient CD40 multimerization and enhanced antitumor activity. To optimize this interaction, we developed 2141-V11, a novel anti-CD40 antibody Fc-engineered to increase binding affinity for FcγRIIB, resulting in effective antitumor activity in both in vivo and in a recent first-in-human phase I trial (NCT04059588). Non-muscle invasive bladder cancer (NMIBC) is the most common presentation of bladder cancer, with a high risk of recurrence and progression despite optimal surgical interventions and standard therapies. Bacillus Calmette-Guerin (BCG) intravesical treatment has been the standard of care for NMIBC over the last five decades. However, 75% of patients ultimately become unresponsive to this therapy, leaving limited curative options aside from complete radical cystectomy. Using several preclinical bladder cancer models, including BCG-unresponsive disease, we found that intravesical administration of 2141-V11 induces durable anti-tumor immunity without systemic toxicity. Based on these findings, we initiated a Phase I study of intravesical 2141-V11 for the treatment of BCG-unresponsive NMIBC. Methods: This is an investigator-initiated Phase I, open-label, dose-escalation study to evaluate the safety and tolerability of intravesical 2141-V11 in patients with BCG-unresponsive NMIBC (N=25) who are ineligible for or decline radical cystectomy (NCT05126472). Following complete transurethral resection, intravesical 2141-V11 is administered once weekly for three doses, with re-treatment eligibility at week 13 and 25, based on disease status determined by on-treatment biopsies. The study follows an MCRM dose escalation design with five dose levels (0.7, 2.0, 7.0, 21.0 and 70.0 mg). Primary endpoints include safety and dose tolerability to determine maximal tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Secondary endpoints involve pharmacokinetic profiling and preliminary evaluation of clinical activity. Exploratory objectives include investigation of biological markers of drug activity in pre- and post-treatment tissue biopsies and urine biospecimens. As of the data cutoff on 12/20/23, 80% of the planned patients (n=20) have been enrolled, with no dose-limiting toxicities observed. Accrual completion is expected by the first quarter of 2024, with ongoing analysis of urine immune profiling, cytokine analysis, as well as single-cell spatial phenotyping in pre- and post-treatment samples. Citation Format: Juan C. Osorio, Muneeb Alam, Jeffrey Wong, David Knorr, Lucas Blanchard, Juan C. Angulo-Lozano, Karissa Whiting, Venkatraman E. Seshan, Timothy F. Donahue, Eugene K. Cha, Alvin C. Goh, Robert Smith, Guido Dalbagni, Christian Hernandez, Melissa McCarter, Eugene J. Pietzak, Jonathan E. Rosenberg, Jeffrey V. Ravetch, Bernard H. Bochner. Phase I study of intravesical Fc-optimized anti-CD40 agonist antibody 2141-V11 for non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG) therapy [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 CT086.

Revolutionizing Treatment: Breakthrough Approaches for BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer.

Bladder cancer is the 10th most popular cancer in the world, and non-muscle-invasive bladder cancer (NMIBC) is diagnosed in ~80% of all cases. Treatments for NMIBC include transurethral resection of the bladder tumor (TURBT) and intravesical instillations of Bacillus Calmette-Guérin (BCG). Treatment of BCG-unresponsive tumors is scarce and usually leads to Radical Cystectomy. In this paper, we review recent advancements in conservative treatment of BCG-unresponsive tumors. The main focus of the paper is FDA-approved medications: Pembrolizumab and Nadofaragene Firadenovec (Adstiladrin). Other, less researched therapeutic possibilities are also included, namely: N-803 immunotherapy, TAR-200 and TAR-210 intravesical delivery systems and combined Cabazitaxel, Gemcitabine and Cisplatin chemotherapy. Conservative treatment and delaying radical cystectomy would greatly benefit patients' quality of life; it is undoubtedly the future of BCG-unresponsive NMIBC.

Patterns of treatment of high-risk BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) patients among Arab urologists.

To understand the treatment plans suggested for BCG-unresponsive non-muscle invasive disease (NMIBC) patients in the Arab countries and therapeutic decisions applied for BCG-naive patients during BCG shortage time. A 10-minute online survey was distributed through the Arab Association of Urology (AAU) office to urologists in the Arab countries who treat patients with NMIBC. One hundred six urologists responded to the survey. The majority of urologists had treated, in the past 6 months, > 10 patients with NMIBC who were considered BCG-unresponsive (55% of respondents). Radical cystectomy (RC) was the most popular treatment option (recommended by 50%) for these patients. This was followed by intravesical chemotherapy (30%), repeat BCG therapy (12%), resection with ongoing surveillance (8%). Clinical trials and intravenous checkpoint inhibitors were never selected. The most preferred intravesical chemotherapy was by ranking: 60% gemcitabine, 19% mitomycin C, 8% docetaxel, 8% gemcitabine/docetaxel, 4% sequential gemcitabine/mitomycin C, and 1% valrubicin. The use of intravesical chemotherapy appears limited by Arab urologists due to concerns regarding clinical efficacy (fear of progression) and the lack of clear recommendations by urology societies. Given the BCG shortage, which may vary per Arab country, Arab urologists have adjusted by prioritizing BCG for T1 and carcinoma in situ (CIS) patients over Ta, adapting intravesical chemotherapy, and reducing the dose/strength of BCG administered. Most physicians report an eagerness to utilize novel therapies to address the BCG deficit, especially to try intravesical chemotherapy. Even though Arab urologists are in the majority of cases selecting RC for BCG-unresponsive cases, one-third of them are most recently initiating intravesical chemotherapy as an alternative option. To further assist Arab urologists in the appropriate selection of BCG unresponsive high risk NMIBC patient treatments, enhanced education and pathway protocols are needed.

Radiotherapy Combined with a Radiosensitizer for Bacillus Calmette-Guérin–unresponsive Non–muscle-invasive Carcinoma In Situ Bladder Cancer: An Open-label, Single-arm, Multicenter, Phase 2 European Organisation for Research and Treatment of Cancer Trial

Radical cystectomy with pelvic lymph node dissection and urinary diversion is the standard of care for patients with bacillus Calmette-Guérin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC). However, many patients are unwilling or unable to undergo such major surgery associated with high morbidity and a negative impact on quality of life. Chemoradiotherapy is an established treatment option for muscle-invasive bladder cancer. However, it has not been investigated adequately in NMIBC until now. The European Organisation for Research and Treatment of Cancer (EORTC) 2235 study (NCT06310369) is designed as a multicenter, prospective, international, phase 2 trial of moderate hypofractionated radiotherapy combined with a radiosensitizer in BCG-unresponsive NMIBC patients with carcinoma in situ (CIS) who are not eligible for or declined to undergo radical cystectomy. Patients who have received nadofaragene firadenovec or TAR-200 are eligible. The primary endpoint is the 6-mo complete response (CR) rate defined by the absence of CIS proven by a control biopsy of the bladder. The secondary endpoints include overall survival, progression-free survival, durability of CR, grade 3–4 adverse events rate, patients’ quality of life, and organ preservation rate. Patient summaryIntravesical instillation of bacillus Calmette-Guérin is the standard treatment of non–muscle-invasive, also coined as superficial, bladder cancer. In case the cancer recurs, even superficially, there is no other proven treatment than a radical cystectomy—the surgical removal of the bladder. Although the surgical technique has improved dramatically over the past few years, it remains contraindicated in patients with severe comorbidities. In addition, because it affects the quality of life, patients may reject this option. This study will assess the efficacy of external beam radiotherapy, a robust alternative to surgery in muscle-invasive bladder cancer. Radiotherapy will be administered 5 d a week for 4 wk. It will be associated with a “radiosensitizer,” an intravenous or oral drug, during the radiotherapy treatment. The study will measure the proportion of patients remaining recurrence free at 6 mo and thereafter. It will also evaluate the safety of the treatment and its impact on quality of life.

Correlation of urinary comprehensive genomic profile with risk of recurrence of BCG-unresponsive non-muscle invasive bladder cancer treated with atezolizumab in SWOG S1605.

529 Background: Radical cystectomy is recommended for patients with BCG-unresponsive (BU) non-muscle invasive bladder cancer (NMIBC) due to high risk of progression. Improved methods for assessing these risks would greatly facilitate the potential for bladder preservation. Here, we tested the capacity of the urinary comprehensive genomic profile (uCGP) to predict event-free survival (EFS) in patients with BU-NMIBC treated with atezolizumab in the single arm phase 2 trial SWOG S1605. Methods: Urine was collected from patients with BU NMIBC (CIS, Ta, T1) treated with at least one dose of intravenous atezolizumab at baseline and before the 5th cycle of therapy (3 months). The uCGP was assessed using UroAmp (Convergent Genomics). Risk scores for recurrence at baseline and at 3 months were calculated by a prespecified machine learning algorithm incorporating alterations in 60 genes and low pass whole genome sequencing, and categorized as high versus low. Molecular response was classified based on change in uCGP between the two time points. Risk scores and molecular response were submitted to SWOG for clinical correlation with EFS using a Cox model, adjusting for CIS status. Time to event was calculated from date of study entry (baseline risk) or from the 2nd collection time (3-month risk) to first high grade (HG) recurrence or persistent CIS at 3 months. Death unrelated to bladder cancer and patients last known to be alive without HG recurrence were censored at date of last visit. Results: Samples were provided at baseline in 89 patients and before the 5th cycle in 77; 68 had both samples available for paired analysis. The risk score at baseline was classified as high in 69% of samples (73% for CIS ±Ta/T1 and 62% for Ta/T1). At 12 and 18 months the EFS probabilities were 26% and 23% for high-risk and 67% and 51% for low-risk patients, respectively, with a HR of 2.82 (95% CI: 1.58, 5.03; p<0.001). The risk score at the 3-month timepoint was classified as high in 81% of samples, and the EFS probabilities at 12 and 18 months after urine collection were 26% and 22% for high-risk and 80% and 72% for low-risk patients, respectively, with a HR of 3.39 (95% CI: 1.41, 8.13; p<0.006). Molecular response to treatment was classified as complete (CR) in 8%, partial (PR) in 14%, stable (SD) in 25% and progression (PD) in 46%, with 7% having no detectable genomic abnormalities at both time points. Clinical recurrence was observed by 18 months in 0/6 patients with CR, 7/9 (78%) with PR, 11/14 (79%) with SD and 25/33 (76%) with PD by genomic profile. Conclusions: This study suggests that uCGP at baseline and after 4 cycles of treatment can identify genomic patterns associated with an increased risk of HG persistence, recurrence or progression in BU NMIBC treated with immune checkpoint inhibition. Future studies will determine if this can be used to guide early treatment intensification.

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 .