BCG-unresponsive Non-muscle Invasive Bladder Cancer Research Articles

MP16-02 PHASE III TRIAL OF INTRAVESICAL NADOFARAGENE FIRADENOVEC IN PATIENTS WITH HIGH-GRADE, BCG-UNRESPONSIVE, NON-MUSCLE INVASIVE BLADDER CANCER: TWO YEAR FOLLOW-UP IN THE TA/T1 COHORT

You have accessJournal of UrologyBladder Cancer: Non-invasive II (MP16)1 Sep 2021MP16-02 PHASE III TRIAL OF INTRAVESICAL NADOFARAGENE FIRADENOVEC IN PATIENTS WITH HIGH-GRADE, BCG-UNRESPONSIVE, NON-MUSCLE INVASIVE BLADDER CANCER: TWO YEAR FOLLOW-UP IN THE TA/T1 COHORT Yair Lotan, Anne K. Schuckman, Stephen A. Boorjian, Katherine E. Cilwa, and Colin P. N. Dinney Yair LotanYair Lotan More articles by this author , Anne K. SchuckmanAnne K. Schuckman More articles by this author , Stephen A. BoorjianStephen A. Boorjian More articles by this author , Katherine E. CilwaKatherine E. Cilwa More articles by this author , and Colin P. N. DinneyColin P. N. Dinney More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002001.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Patients (pts) with high-grade (HG) non-muscle invasive bladder cancer (NMIBC) who develop BCG-unresponsive disease are faced with limited therapeutic options. Nadofaragene firadenovec is a novel gene-mediated therapy that confers the human IFNα2b gene to bladder urothelium following intravesical instillation and results in prolonged, localized expression of IFNα2b. Phase 3 primary efficacy, safety, and durable responses were demonstrated in the published, initial findings. Herein, 24 month (mos) follow-up data are presented for the HG Ta/T1 cohort. METHODS: A multicenter, open-label Phase 3 trial enrolled pts into two cohorts with BCG-unresponsive NMIBC: carcinoma in situ (CIS±Ta/T1) and HG Ta/T1 alone. For the Ta/T1 cohort, 48 pts and 50 were included in the efficacy and safety analyses. Nadofaragene (3x1011 vp/mL [75 mL]) was administered once every 3 mos for up to 4 doses. The protocol mandated a 5-site (dome, trigone, right and left lateral walls, posterior wall) biopsy at 12 mos. All pts with an absence of HG disease recurrence at 12 mos were offered continued treatment once every 3 mos at the investigator’s discretion. Pts who did not continue treatment beyond 12 mos were followed. RESULTS: As of the September 2020 data cutoff, 9/48 (18.8%) pts had received 24 mos of treatment, and 33/48 (68.8%) remained on study with restricted-mean follow-up of 23.5 mos (95% CI 22.9-24.1). Of 48 pts, 35 (72.9%), 21 (43.8%), 16 (33.3%) were HGRF at 3, 12, and 24 mos. Of those HGRF at 3 mos, 16/35 (45.7%) were HGRF at 24 mos and the median duration of HGRFS was 19.8 months. Cystectomy-free survival was 69.8% (95% CI 54.3-80.9) and overall survival was 93.2% (95% CI 80.4–97.8) when estimated via KM at 24 mos, with 11/48 (22.9%) pts having underwent cystectomy. The most common drug-related adverse events (AEs) were 26% instillation site discharge, 16% dysuria, 14% bladder spasm, and 14% micturition urgency. The majority were Grades 1/2. One (2%) pt had any AE leading to discontinuation. There was one Grade 4 AE (not related to study drug/procedure) and no adverse events occurred leading to pt death. CONCLUSIONS: Nadofaragene firadenovec was well tolerated and demonstrates durability of response in pts with HG Ta/T1, BCG-unresponsive NMIBC in 24 mos follow-up after first intravesical treatment. Clinical trial information: NCT02773849. Source of Funding: FKD Therapies Oy © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e296-e296 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yair Lotan More articles by this author Anne K. Schuckman More articles by this author Stephen A. Boorjian More articles by this author Katherine E. Cilwa More articles by this author Colin P. N. Dinney More articles by this author Expand All Advertisement Loading ...

MP16-01 EFFICACY OF INTRAVESICAL NADOFARAGENE FIRADENOVEC FOR PATIENTS WITH CARCINOMA IN SITU (CIS), BCG-UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC): LONGER-TERM FOLLOW-UP FROM THE PHASE III TRIAL

You have accessJournal of UrologyBladder Cancer: Non-invasive II (MP16)1 Sep 2021MP16-01 EFFICACY OF INTRAVESICAL NADOFARAGENE FIRADENOVEC FOR PATIENTS WITH CARCINOMA IN SITU (CIS), BCG-UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC): LONGER-TERM FOLLOW-UP FROM THE PHASE III TRIAL Anne K. Schuckman, Yair Lotan, Stephen A. Boorjian, Katherine E. Cilwa, and Colin P. N. Dinney Anne K. SchuckmanAnne K. Schuckman More articles by this author , Yair LotanYair Lotan More articles by this author , Stephen A. BoorjianStephen A. Boorjian More articles by this author , Katherine E. CilwaKatherine E. Cilwa More articles by this author , and Colin P. N. DinneyColin P. N. Dinney More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002001.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Despite optimal treatment (tx), patients (pts) with BCG-unresponsive NMIBC remain at significant risk for recurrence and progression and thus an unmet medical need exists for local, effective, bladder-preserving tx options. Nadofaragene firadenovec is a non-replicating recombinant type 5 adenovirus vector-based gene therapy that delivers a copy of the human IFNα2b gene. The Phase 3 study assessed its safety and efficacy in 157 pts with high-grade (HG), BCG-unresponsive NMIBC and met its primary endpoint with 53.4% of pts with CIS±Ta/T1 achieving a complete response (CR), all by 3 mos. Longer-term follow-up results for the CIS±Ta/T1 cohort is reported here. METHODS: The open-label Phase 3 study enrolled 107 BCG-unresponsive, CIS±Ta/T1 (CIS with/without HG Ta or T1) pts. Efficacy analysis included 103 pts. Nadofaragene (3x1011 vp/mL [75 mL]) was administered once every 3 mos for up to 4 doses. The protocol mandated a 5-site biopsy at 12 mos. All pts without HG recurrence at 12 mos were offered continued tx once every 3 mos beyond 12 mos at the investigator’s discretion. Pts who did not receive further tx were followed. RESULTS: As of the data cutoff in September 2020, 64/103 (62.1%) of the cohort remained on study with restricted-mean follow up of 23.5 mos (95% CI 22.9-24.0) and 18/103 (17.5%) pts had received 24 mos of tx. At 24 mos after the first dose, 20/103 (19.4%) pts continued to remain free of HG recurrence. Of the 55 CIS±Ta/T1 pts who achieved a CR following treatment, 20 (36.4%) remained free of HG recurrence at 24 months and the median duration of HGRFS was 12.2 months. By 24 mos 33/103 (32%) pts had undergone cystectomy, for a KM cystectomy-free survival of 64.6% (95% CI 54.1-73.3) and overall survival of 94.4% (95% CI 87.0-97.6). Nadofaragene firadenovec was well tolerated. Overall, 1 grade 4 non-tx-related AE (sepsis) was reported and there were no grade 5 AEs. The most common drug-related AEs were instillation site discharge 24.3%, fatigue 23.4%, bladder spasm 17.8%, and micturition urgency 16.8%. The majority were Grades 1/2. Two (1.9%) pts discontinued due to drug-related AEs (1 instillation site discharge, 1 bladder spasm). CONCLUSIONS: Nadofaragene firadenovec instilled intravesically once every 3 mos demonstrates sustained durability of response with longer follow-up in pts with HG, BCG-unresponsive NMIBC. Clinical trial information: NCT02773849. Source of Funding: FKD Therapies Oy © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e296-e296 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Anne K. Schuckman More articles by this author Yair Lotan More articles by this author Stephen A. Boorjian More articles by this author Katherine E. Cilwa More articles by this author Colin P. N. Dinney More articles by this author Expand All Advertisement Loading ...

PD09-02 ANTI-ADENOVIRAL ANTIBODY LEVELS PREDICT NADOFARAGENE FIRADENOVEC RESPONSE IN BCG-UNRESPONSIVE NMIBC: RESULTS FROM A PHASE 3 TRIAL

PD09-02 ANTI-ADENOVIRAL ANTIBODY LEVELS PREDICT NADOFARAGENE FIRADENOVEC RESPONSE IN BCG-UNRESPONSIVE NMIBC: RESULTS FROM A PHASE 3 TRIAL

Bacillus Calmette-Guérin-unresponsive non-muscle invasive bladder cancer outcomes in patients without radical cystectomy.

Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) is a newly defined subtype that is unlikely to benefit from BCG rechallenge. Radical cystectomy is currently recommended for BCG-unresponsive NMIBC; however, a certain proportion of these patients can be managed with treatments other than that. Herein, we conducted a multicenter retrospective study to analyze the clinical outcomes of BCG-unresponsive NMIBC patients who did not receive radical cystectomy. Of the 141 BCG-unresponsive NMIBC patients, 94 (66.7%) received treatment except radical cystectomy. Survival outcomes were calculated from the date of diagnosis using the Kaplan-Meier method and compared using the log-rank test. Prognostic factors were identified using the multivariate Cox regression model. This group was further classified into three groups according to the number of risk factors, and survival outcomes were compared. Multivariate analyses identified low estimated glomerular filtration rate (< 45ml/min/1.73 m2) and large tumor size (≥ 30mm) before BCG induction as independent poor prognostic factors for progression-free survival and overall survival, while the latter was also an independent factor for cancer-specific survival. The presence of variant histology was an independent poor prognostic factor for overall survival. The high-risk non-cystectomy group showed a significantly poor prognosis for progression-free survival (hazard ratio: 7.61, 95% confidence interval: 2.11-27.5), cancer-specific survival (10.4, 0.54-70.02), and overall survival (8.28, 1.82-37.7). Our findings suggest that patients with renal impairment and large tumors should undergo radical cystectomy if the complications and intentions of the patients allow so.

Approaches to Non-Muscle-Invasive Bladder Cancer.

Non-muscle-invasive bladder cancer (NMIBC) is a heterogenous malignancy with high recurrence and progression rates, which necessitate uniform recommendations for diagnosis and management. Herein, we review the literature, with an emphasis on guidelines and contemporary diagnostic techniques and interventions. Guidelines around the world have adopted a schema which risk-stratify cases at diagnosis, to offer evidence-based treatment and surveillance recommendations. Enhanced endoscopic technologies can improve detection of NMIBC and reduce recurrence. The present Bacillus Calmette-Guerin (BCG) shortage in the USA has led to new strategies to prioritize the most high-risk cases. The entity of BCG-unresponsive high-risk NMIBC remains a challenge to manage, with multiple novel treatments under investigation; fortunately, new therapies have been approved, such as immune checkpoint inhibitors, and others are showing tremendous promise. The standardization of NMIBC management, with evolving detection techniques and therapeutics, offers great potential to improve patient outcomes and survivorship.

Checkpoint inhibitors in BCG-unresponsive nonmuscle invasive bladder cancer: can they help spare the bladder?

Intravesical BCGtherapy has been for years, the standard of care in nonmuscle-invasive bladder cancer. But upon recurrence/relapse, radical cystectomy is imposed, due to the paucity of other therapeutic options. Immunotherapy has been revolutionizing cancer treatment, and its indications continue to broaden. It has been approved for the treatment of advanced urothelial cancer of the bladder, mainly as a second-line therapy. Its activity is being studied in nonmuscle-invasive bladder cancer that is not responsive to BCG; we herein report the trials investigating these checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab, durvalumab andavelumab) in this particular setting.

PCN74 Long-Term Cost-Effectiveness of Nadofaragene Firadenovec and Oportuzumab Monatox for Treatment of Bacillus Calmette-Guerin (BCG)-Unresponsive, Non-Muscle Invasive Bladder Cancer (NMIBC)

Nadofaragene firadenovec (NADO) and oportuzumab monatox (OPOR) are new treatments for bladder cancer unresponsive to BCG therapy. To evaluate the long-term cost-effectiveness of NADO and OPOR compared with a hypothetical bladder cancer treatment (HT) in BCG-unresponsive NMIBC in 2 patient populations: those with 1) carcinoma in situ (CIS) ± high-grade Ta/T1 and 2) high-grade Ta/T1 alone (Ta/T1). Pembrolizumab (PEM) was also evaluated in CIS, and gemcitabine ± docetaxel (GEM/DOC) in both populations. A semi-Markov model was developed, employing 3-month cycles over a lifetime horizon, from a healthcare sector perspective. Model inputs were obtained through manufacturer- submitted evidence, systematic literature reviews, and clinical expert opinion. NADO price was based on annual PEM price and OPOR price was a manufacturer provided placeholder price. Primary outcomes, discounted at 3% annually, included total costs (TC), quality-adjusted life years gained (QALY), equal value of life years gained (evLYG), and cost/QALY compared to HT. One-way and probabilistic sensitivity analyses were conducted to evaluate uncertainty. For CIS population: NADO had $308,000 TC, 5.17 QALY, 5.26 evLYG, and $151,000 cost/QALY; OPOR had $310,000 TC, 4.69 QALY, 4.73 evLYG, and $382,000 cost/QALY; PEM had $265,000 TC, 5.04 QALY, 5.12 evLYG, and $114,000 cost/QALY, and GEM/DOC had $172,000 TC, 5.88 QALY, 6.00 evLYG, and dominated HT. For Ta/T1 population: NADO had $302,000 TC, 5.52 QALY, 5.64 evLYG, and $93,000 cost/QALY; OPOR had $302,000 TC, 5.23 QALY, 5.32 evLYG, and $123,000 cost/QALY; and GEM/DOC had $165,000 TC, 5.83 QALY, 5.95 evLYG, and dominated HT. Key uncertainty drivers were probabilities of disease progression to MIBC, NMIBC recurrence beyond 12 months and initial treatment efficacy. NADO and OPOR may provide bladder-sparing therapeutic alternatives for BCG- unresponsive NMIBC patients. Pricing of these drugs will determine whether they are cost effective at commonly accepted thresholds.

P0745 - Subgroup analyses of the phase 3 study of intravesical nadofaragene firadenovec in patients with high-grade, BCG-unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC)

P0745 - Subgroup analyses of the phase 3 study of intravesical nadofaragene firadenovec in patients with high-grade, BCG-unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC)

P0746 - Significant anti-adenovirus antibody response positively correlates with efficacy in patients treated with nadofaragene firadenovec for high-grade BCG-unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC)

P0746 - Significant anti-adenovirus antibody response positively correlates with efficacy in patients treated with nadofaragene firadenovec for high-grade BCG-unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC)

Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816).

4541 Background: Radical cystectomy (RC) is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC), but many patients are unfit for surgery or elect bladder preservation. This trial was designed to evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This single arm phase II registration trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year aimed to enroll 135 (70 CIS and 65 non-CIS) eligible patients with histologically proven BCG-unresponsive high risk NMIBC who were unfit for or declined RC. Here we report the 18 month results for all eligible patients who received at least one protocol treatment. The co-primary endpoints were pathological complete response (CR) rate at 6 months in patients with CIS (reported at ASCO 2020), and event-free survival (EFS) in all patients at 18 months using Kaplan-Meier methods (KM), conditional on a positive CIS response rate. A sample size of 135 evaluable patients provided 93% statistical power for detecting a 30% 18-month EFS rate versus 20% using a one-sided alpha = 0.05. EFS in the subset with Ta/T1 disease and duration of response in CIS patients were secondary endpoints. Results: 172 patients were enrolled, 166 received at least one dose of atezolizumab and are included in the safety analysis, and, of those, 128 were eligible and included in the efficacy analysis. As previously reported, 20 (27%) out of 74 patients with CIS attained a pathologic CR at 6 months. The KM estimate of 12 month (actual 11.9 mo) duration of response after 6 month CR for CIS patients was 54% (95% CI 30%, 78%) and the median duration of response was 16.5 months. The KM EFS rate at 18 months in 74 patients with CIS was 17% (90% CI 9%, 25%). The 18 month KM EFS rate in the overall population of 128 patients with Ta, T1 and CIS was 29% (90% CI 22%, 36%). The 18 month actuarial EFS rate in 54 patients with Ta/T1 disease was 45% (90% CI 34, 57%). Any possibly or probably treatment-related adverse event (TRAE) was observed in 142 out of 166 (86%) patients who received any atezolizumab regardless of eligibilty. The most frequent TRAEs were fatigue 72 (43%), diarrhea 34 (20%), and anemia 38 (23%). Grade 3-5 TRAEs occurred in 28 (17%) patients, including rash in 4 (2%), hyponatremia in 4 (2%), hypertension in 3 (2%) and elevated liver function tests in 3 (2%). There were two treatment-related deaths (sepsis and respiratory failure due to myasthenia gravis). Conclusions: The observed response of atezolizumab at 6 and 18 months in patients with BCG-unresponsive CIS suggests that this could be a valuable treatment to address a critical unmet need in this patient population. The 18 month EFS in patients with Ta/T1 disease suggests activity in this patient subset. This trial provided no new safety concerns. Funding: NIH/NCI grants: CA180888, CA180819, CA180820, CA180821, CA180863 and in part by Genentech. Clinical trial information: NCT02844816.

The current landscape of salvage therapies for patients with bacillus Calmette-Guérin unresponsive nonmuscle invasive bladder cancer.

Although radical cystectomy represents the gold standard treatment for patients with high-risk nonmuscle invasive bladder cancer (NMIBC) whose disease does not respond to bacillus Calmette-Guérin (BCG), many patients are unable or unwilling to undergo surgery. The need remains for effective bladder-preserving therapies. This review aims to describe existing treatments, contemporary research in this field and ongoing trials of salvage therapies for patients with BCG-unresponsive NMIBC. Intravesical chemotherapy has been utilized frequently in this setting. Emerging data on combination regimens such as intravesical gemcitabine and docetaxel and intravesical cabazitaxel, gemcitabine and cisplatin are promising; nevertheless, larger, prospective trials are needed. Meanwhile, the intravenous checkpoint inhibitor pembrolizumab was recently FDA-approved for patients BCG-unresponsive NMIBC. Encouraging clinical trial results for intravesical nadofaragene firadenovec, oportuzumab monatox and ALT-803 + BCG have been released, while data from trials of other treatment strategies, including novel chemotherapy and drug delivery, augmented BCG immunotherapy, adenoviral and gene therapy, targeted therapy, and combination systemic immunotherapy with intravesical agents, are eagerly awaited. Several novel salvage therapies offer promise for patients with BCG-unresponsive NMIBC. Patient selection, efficacy, safety, cost and ease of administration must be carefully considered to determine the optimal treatment approach.

Phase II/III clinical results of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) patients.

510 Background: Patients with NMIBC CIS unresponsive to BCG have limited treatment options. N-803 (Anktiva) is a mutant IL-15-based immunostimulatory fusion protein complex (IL-15RαFc) that promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells. Phase Ib data in BCG-naive patients with NMIBC demonstrate that intravesical administration of N-803 with BCG induced complete response in all patients, without recurrences for the study duration of 24 months. An open-label, 3 cohort multicenter phase II/III study (QUILT 3.032) of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825) was opened. We report here the interim analysis of Cohort A, BCG-unresponsive (CIS) [with or without Ta or T1 disease], as of December 2020 data cutoff. Methods: All treated patients received intravesical N-803 plus BCG, consistent with the standard induction/maintenance treatment schedule. The primary endpoint for Cohort A of this phase II/III study is incidence of complete response (CR) of CIS at any time. Results: To date, 80 patients have enrolled in cohort A of this phase II/III trial. Evaluable analysis at this time shows CR rate at any time of 72% (N=51/71); for patients achieving CR, the probability of maintaining a CR for 12 months is 59%, with a median duration of complete response of 19.2 (7.6, 26.4) months. Low-grade treatment related AEs include dysuria, hematuria, and pollakiurua (all 16%), urgency (14%), and bladder spasm (8%), all other AEs were seen at 6% or less. A total of 9 subjects experienced at least 1 treatment emergent SAE (Severe Adverse event), the SAE rate is 1% for any given AE. No treatment emergent SAE’s were considered treatment related. No immune related SAE’s have been seen. To date, 10/80 (12.5%) patients proceeded to cystectomy in this BCG unresponsive population. Conclusions:With a CR rate of 72%, N-803 has met its primary endpoint with 59% probability of CR patients maintaining CR for at least 12 months. With the observed strong efficacy and an SAE rate of 1%, N-803 represents a novel treatment option for BCG unresponsive CIS with a favorable benefit:risk ratio, in a therapeutically challenging disease. Clinical trial information: NCT03022825.

A phase I trial of chemoimmunotherapy combining bacillus Calmette-Guerin (BCG) and intravesical gemcitabine for patients with BCG-relapsing high-grade nonmuscle-invasive bladder cancer.

TPS509 Background: Intravesical BCG is the most effective treatment for high-grade non-muscle invasive bladder cancer (NMIBC), yet recurrences are common. Patients with BCG-relapsing NMIBC are often re-treated with BCG or BCG with interferon (IFN) with an expected response rate of only 40–60%. Several studies show that a major mechanism of resistance to BCG is high levels of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the pretreatment tumor microenvironment. Gemcitabine is a commonly used intravesical treatment for NMIBC that, in addition to direct anti-tumor cytotoxic effects, may also reduce MDSCs and Tregs. Prior trials combining BCG with intravesical mitomycin C have shown improved efficacy over BCG alone but with higher toxicity. While gemcitabine has been shown to be better tolerated than mitomycin as an intravesical treatment, no study has looked at combined BCG and intravesical gemcitabine. We hypothesize that combining BCG and intravesical gemcitabine will be well tolerated and result in higher response rates by reducing levels of MDSCs and Tregs. A novel aspect of our trial design is the use of a modified continual reassessment method to more accurately identify the maximum tolerated dose instead of the traditional 3 + 3 design used in most NMIBC phase I trials. Methods: This is an investigator-initiated phase I trial (NCT04179162) that will study the safety of alternating intravesical gemcitabine and BCG. Inclusion and exclusion criteria are designed so most patients who would ordinarily be re-treated with BCG or BCG/IFN would be eligible. Patients must have recurrent high-grade NMIBC within 24 months of their last BCG treatment without meeting the criteria for BCG-unresponsive NMIBC. Intravesical gemcitabine is given twice a week on weeks 1, 4, 7, and 10, for a total of 8 doses. BCG (50 mg) is given once a week on weeks 2, 3, 5, 6, 8, and 9, for a total of 6 doses. The trial is monitored using a modified continual reassessment method with increasing dose levels of gemcitabine (500 mg, 1,000 mg, 1,500 mg, and 2,000 mg) being evaluated. Adverse events are assessed using the Common Terminology Criteria for Adverse Events version 5.0. The primary objective is to determine the maximum tolerated dose of this combination to inform our planned phase II trial. Correlative studies will look at the immunomodulating effects of gemcitabine by evaluating changes in immune cell populations in serial blood and urine specimens. Tissue and urine will also be evaluated for molecular determinants of response and resistance to the combination. The trial is open to enrollment with 10 of 25 planned patients accrued to date. Clinical trial information: NCT04179162.

Emerging treatments for bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer.

Intravesical bacillus Calmette–Guérin (BCG) immunotherapy has been the gold standard adjuvant treatment for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG immunotherapy prevents disease recurrence and progression to muscle-invasive disease following TURBT. Although most patients initially respond well to intravesical BCG, considerable concern has been raised for patients with BCG failure who are refractory or recur in 6 months after their last BCG, which implies ‘BCG-unresponsiveness’. Based on current clinical guidelines, early radical cystectomy (RC) is recommended to treat BCG-unresponsive NMIBC. However, due to the high risk of morbidity and mortality of RC and patients' desire to preserve their own bladder, there is a critical unmet need for alternative conservative treatments as bladder-sparing strategies in BCG-unresponsive patients. Trials for effective bladder-sparing treatments are ongoing, and several novel agents have been recently tested in the NMIBC setting. The goal of this review is to introduce and summarize recently reported novel and emerging drugs and ongoing clinical trials for BCG-unresponsive NMIBC.

Novel and emerging approaches in the management of non-muscle invasive urothelial carcinoma.

Non-muscle invasive bladder cancer (NMIBC) has traditionally been managed with transurethral resection followed by intravesical chemotherapy and/or bacillus Calmette–Guerin (BCG) in a risk-adapted manner. These tumors commonly recur and can progress potentially to lethal muscle invasive disease. A major unmet need in the field of NMIBC is bladder preserving therapy for recurrent high-grade NMIBC after adequate intravesical BCG therapy. The current gold standard treatment for these BCG-unresponsive patients is radical cystectomy, which is associated with considerable morbidity and mortality, particularly in older and frailer patients. It is therefore critical to provide alternative treatment options with acceptable oncological outcomes. In this review we explore novel bladder-sparing treatment options including combination intravesical therapy, enhanced instillation methods, immunotherapy, gene therapy, targeted therapy, photodynamic therapy and BCG variants across the spectrum of NMIBC disease states, ranging from low grade BCG-naïve patients through to high-grade BCG-unresponsive NMIBC.

Immunotherapy of Bladder Cancer

Bladder cancer used to be the only cancer treated by immunotherapy in form of intravesical BCG. Since approval of BCG for Non muscle invasive bladder cancer (NMIBC), there has been significant advancement in our knowledge about immune alteration in cancer and availability of immunotherapeutic agents. Tumor induced cell mediated immunosuppression is identified as a key factor for development and progression of cancer. Immune suppression in bladder cancer is predominantly through Macrophages. Myeloid derived suppressor cell, NK cells, Treg and expression of immune checkpoint receptor inhibitors also contribute to immune suppression. BCG induces innate immune response and its efficacy is limited to NMIBC. Novel immunotherapeutic agents evaluated in bladder cancer are administered locally or systemically to induce innate or adaptive immune response. Systemic administration of antibodies against PD-1/PD-L1 axis are now approved for treatment of locally advanced/metastatic bladder cancer as a first line as well as second line therapy. Pembrolizumab is also approved for BCG unresponsive NMIBC. Since response to immunotherapy are neither uniform nor universal, attempts are made to identify prognostic and predictive biomarkers. Identified biomarkers lack desired specificity and sensitivity. Several immune approaches using innate as well as adaptive mechanism are under evaluation to improve outcome of intravesical BCG or immune check point receptor inhibitors.

Role of immunotherapy in Bacillus Calmette-Guérin unresponsive: non-muscle invasive bladder cancer.

Bacillus Calmette-Guérin (BCG) is recommended as the first-line treatment option for intermediate to high risk non-muscle invasive bladder cancer (NMIBC) by current clinical guidelines. However, despite the intravesical instillation of BCG, a significant proportion of patients with intermediate to high risk NMIBC develop intravesical recurrence. Moreover, the treatment of BCG-unresponsive NMIBC is currently challenging. There are no reliable treatment options for these patients with BCG-unresponsive NMIBC except radical cystectomy, which reported to show acceptable oncological outcomes. In this regards, reliable and safe non-invasive or less-invasive treatment options with acceptable oncological outcomes are awaited for the treatment of BCG-unresponsive NMIBC. The treatment of advanced or metastatic urothelial carcinoma has greatly advanced following the recent introduction of immunotherapeutic agents. These advancements have triggered an increasing interest in the use of immunotherapeutic agents for NMIBC, and especially for BCG-unresponsive NMIBC. The current review article aims to introduce and discuss the cutting-edge knowledge on the role of immunotherapy in BCG-unresponsive NMIBC and the currently available therapeutic strategies for its treatment. In addition, this article also summarizes the ongoing studies in this field.

Abstract IA20: Intravesical versus systemic therapy: Win, lose, or draw—the future is now for multidisciplinary NMIBC drug development

Abstract In recent years, we have witnessed an explosion in both therapeutic drug development and our understanding of the key biologic drivers and targets in bladder cancer. While new drug approvals have thus far been confined to metastatic patients, several promising agents have fully accrued key FDA registration studies in the BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) population. Initial early-response data in the carcinoma in situ (CIS) populations demonstrate clear signals of activity with long-term follow-up ongoing to assess response durability. Agents administered by either intravesical or systemic routes are among those being assessed. While urologists, medical oncologists, and radiation oncologists have long worked together in the care of muscle-invasive bladder cancer (MIBC) and metastatic bladder cancer patients, an established template of multidisciplinary collaboration in the care of NMIBC patients is lacking. This unknown frontier creates both challenges and immense opportunities. True lasting, impactful progress rarely happens in isolation. This session will utilize data and example cases to illustrate specialty-specific skills and perceptions that define us, must be acknowledged for the biases they create, and ultimately should be embraced as a vehicle to establish functional and collaborative multidisciplinary drug development and clinical care models for NIMIBC patients. Citation Format: Noah M. Hahn. Intravesical versus systemic therapy: Win, lose, or draw—the future is now for multidisciplinary NMIBC drug development [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA20.

Abstract IA22: Realizing the potential of targeted therapy in non-muscle invasive bladder cancer

Abstract Targeted therapies have revolutionized the management of most cancers, but the era of targeted therapy has mostly passed by bladder cancer. Ramicurimab (targeting VEGR) and erdafitinib and infigratinib (both targeting FGFR) have recently provided some reason for optimism that targeted therapies with highly potent inhibitors may yet find a role in advanced bladder cancer. Targeting genomic alterations in FGFR3 holds the most promise, but this molecular event is probably even more relevant in non-muscle invasive bladder cancer (NMIBC), and trials in this space are essential. Similarly, KDMT6a appears to be particularly important in NMIBC, and drugs targeting chromatin modification pathways are likely to be relevant in NMIBC. Novel therapies are also under development that are not specific to an individual cancer's genomic makeup, but instead target specific cancer-related pathways. Such agents include oportuzumab monatox and BC-819. Most clinical trial activity has focused on BCG-unresponsive high-risk NMIBC patients, but this is partly due to the pathway for drug registration, and we are likely to see some of the successful drugs in this disease state move forward to earlier disease states, especially to intermediate-risk patients. These therapies will need to be positioned in the treatment landscape along with other nontargeted intravesical agents such as nadofaragene firadenovec (rAd-IFN) and systemic immune checkpoint blockade. Citation Format: Peter C. Black. Realizing the potential of targeted therapy in non-muscle invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA22.

Abstract A14: Next-generation sequencing of Bacille Calmette-Guerin (BCG)-unresponsive tumors identifies actionable alterations for potential targeted therapy in non-muscle invasive bladder cancer

Abstract Introduction and Objective: Intravesical BCG remains standard of care for patients with intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC). Although most patients initially respond to therapy, there is a group of patients who will experience recurrence and subsequent progression to invasive disease. There are limited treatment options for patients with BCG-unresponsive bladder cancer and alternative therapeutic strategies are needed. Next-generation sequencing helps identify and prioritize therapeutic opportunities for clinical trial of novel targeted agents. Methods: All patients with urothelial carcinoma of the bladder who progressed to muscle-invasive disease after at least one course of intravesical BCG were identified within our institutional genomic database and in The Cancer Genome Atlas (TCGA) dataset. DNA from BCG-treated, chemotherapy naive, secondary MIBC tumors and matched normal DNA underwent targeted exome capture sequencing or whole-exome sequencing. Potentially actionable genomic alterations were defined according to OncoKB levels of evidence for each alteration as a predictive biomarker (OncoKB.org). Results: The cohort comprised 77 secondary MIBC specimens, each from a unique patient. Sixty-six (86%) were male and the median age was 67 years (IQR 61-75). At least one potentially actionable genomic alteration was identified in 85% of the specimens. RTK/MAPK pathway alterations, most commonly FGFR3 (18%) and ERBB2 (15%), were seen in 42% of patients. PIK3CA mutations, seen in 21%, often co-occurred with RTK/MAPK alterations, potentially representing a resistance mechanism to FGFR or ERBB2-directed monotherapy. CDKN2A loss, hypothesized to be a driver of progression in FGFR3-mutated tumors, occurred in 10% of the samples. Alterations in cell cycle regulators were seen in 65% of specimens, of which 40% also had an intact RB gene and could potentially be vulnerable to CDK4/6 inhibitors. MDM2 amplification with “wild-type” TP53 was seen in 13% of specimens that might be sensitive to small-molecule antagonists. Inactivating mutations in histone acetyltransferases, CREBBP or EP300, occurred in 17% of specimens that might confer sensitivity to HDAC inhibitors. Truncating mutations in the SWI/SNF chromatin-modifying complex occurred in 33%, predominately in ARID1A, which we recently reported to be associated with worse recurrence-free survival after BCG. Truncating KDM6A mutations were seen in 19%, which along with ARID1A mutated tumors may be vulnerable to EZH2 inhibitors. Conclusion: Limited effective treatments beyond radical cystectomy are available for BCG-unresponsive NMIBC. Genomic profiling identified several actionable alterations that offer potential therapeutic strategies for management of BCG-unresponsive disease. Targeted therapy for NMIBC patients warrants further investigation as further advances are made in development of more selective systemic inhibitors and improved intravesical drug delivery. Citation Format: Aleksandra Walasek, Nima Almassi, Victor McPherson, Shawn Dason, Nicole Benfante, Tanya Klein, Michael F. Berger, Nikolaus Schultz, Guido Dalbagni, Dean F. Bajorin, Jonathan E. Rosenberg, Hikmat Al-Ahmadie, Bernard H. Bochner, David B. Solit, Gopakumar Iyer, Eugene J. Pietzak. Next-generation sequencing of Bacille Calmette-Guerin (BCG)-unresponsive tumors identifies actionable alterations for potential targeted therapy in non-muscle invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A14.