BCG-unresponsive Non-muscle Invasive Bladder Cancer Research Articles

MP54-03 CORE1: PHASE 2, SINGLE ARM STUDY OF CG0070 COMBINED WITH PEMBROLIZUMAB IN PATIENTS WITH NON MUSCLE INVASIVE BLADDER CANCER (NMIBC) UNRESPONSIVE TO BACILLUS CALMETTE-GUERIN (BCG)

You have accessJournal of UrologyCME1 May 2022MP54-03 CORE1: PHASE 2, SINGLE ARM STUDY OF CG0070 COMBINED WITH PEMBROLIZUMAB IN PATIENTS WITH NON MUSCLE INVASIVE BLADDER CANCER (NMIBC) UNRESPONSIVE TO BACILLUS CALMETTE-GUERIN (BCG) Roger Li, Gary Steinberg, Donald Lamm, Ed M. Uchio, Paras Shah, Ashish M. Kamat, Nataliya Hnat, Michael J. Chisamore, Paola Grandi, and James Burke Roger LiRoger Li More articles by this author , Gary SteinbergGary Steinberg More articles by this author , Donald LammDonald Lamm More articles by this author , Ed M. UchioEd M. Uchio More articles by this author , Paras ShahParas Shah More articles by this author , Ashish M. KamatAshish M. Kamat More articles by this author , Nataliya HnatNataliya Hnat More articles by this author , Michael J. ChisamoreMichael J. Chisamore More articles by this author , Paola GrandiPaola Grandi More articles by this author , and James BurkeJames Burke More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002633.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: CG0070, is an Ad5-based oncolytic vaccine engineered to express GM-CSF and replicate selectively in tumor cells with mutated or deficient RB. The CG0070 mechanism of action includes cell lysis and immunogenic cell death which is enhanced in the presence of GM-CSF. In an open label ph. 2 study, an overall CR rate of 62% and a CR at 12 months (m) of 29% have been observed in pts with high risk NMIBC previously treated with BCG.IV pembrolizumab was recently approved by the FDA for patients with BCG-unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12 m CR rate of ∼20%. This ph. 2 study will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC. METHODS: 35 pts with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravesical CG0070 (1x1012 vp) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Pts with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 of CG0070. Pembrolizumab will be administered up to 24 m. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12 m. Recurrence of HG disease will be enumerated as disease recurrence.The primary endpoint of the study is CR at 12 m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety of the combination. Correlate assessments will include changes in the tumor immune microenvironment, systemic immune induction, viral replication and transgene expression. Baseline expression of PD-L1, coxsackie adenovirus receptor, E2F transcription factor as well as anti-Ad5 Ab titer will be correlated with tumor response. RESULTS: 9 pts have reached the 3 m follow up time point with all 9 achieving a CR (100% CR rate). Of these, 6 pts have reached the 6 m and 3 pts the 9 m landmarks with a CR achieved at all timepoints. Treatment related AE have been limited to transient grade 1-2 urinary frequency. No treatment-related grade 3 or higher AE or SAE have been observed. CONCLUSIONS: The combination of CG0070 and pembrolizumab has been well tolerated with encouraging early efficacy data. An update on this ongoing trial will be provided at the time of presentation. Source of Funding: CG Oncology © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e927 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Roger Li More articles by this author Gary Steinberg More articles by this author Donald Lamm More articles by this author Ed M. Uchio More articles by this author Paras Shah More articles by this author Ashish M. Kamat More articles by this author Nataliya Hnat More articles by this author Michael J. Chisamore More articles by this author Paola Grandi More articles by this author James Burke More articles by this author Expand All Advertisement PDF DownloadLoading ...

IJU this Issue

This issue of International Journal of Urology contains one Review Article, 10 Original Articles, and eight editorial comments. Yuan et al. (Jiangsu, China) updated a meta-analysis for the diagnostic performance of the Vesical Imaging–Reporting And Data System (VI-RADS) for predicting muscle-invasive bladder cancer (MIBC) with 20 studies published between September 2018 and July 2021. VI-RADS was introduced in 2018 to define a standardized approach to imaging and reporting multiparametric magnetic resonance imaging for patients with bladder cancer. The diagnostic performance of the VI-RADS for predicting MIBC was excellent in both cutoff points of the VI-RADS 3 and 4. Multiple image acquisition planes of diffusion-weighted imaging should be given more attention in the VI-RADS. We hope that VI-RADS will become more mature and prevalent, which should lead to better management of bladder cancer via further studies. In the original articles, Nishimura et al. (Nara, Japan) evaluated the clinical outcomes and prognostic factors in Japanese patients with bacillus Calmette-Guerin (BCG)-unresponsive nonmuscle-invasive bladder cancer (NMIBC) who underwent early radical cystectomy (RC) using a large-scale multicenter retrospective study and concluded the highest-risk status among the pre-BCG factors was associated with upstaging to extravesical tumors and poor prognosis, despite early RC procedures. The Japanese Urological Association Clinical Practice Guidelines for Bladder Cancer 2019 recommended that patients with BCG-unresponsive disease are considered unlikely to benefit from further BCG therapy and early RC. This study seems to be one of those with the evidence based on a pathological evaluation. Although some new strategies such as intravesical nadofargene firadenovec gene therapy (Lancet Oncol. 2021; 22: 107–17), pembrolizumab monotherapy (Lancet Oncol. 2021; 22: 919–30) have been reported, there is no doubt that BCG-unresponsive disease is a risk factor and RC will continue to be required in a certain proportion of patients with BCG-unresponsive NMIBC. Kato et al. (Osaka, Japan) evaluated the long-term incidence and clinical features of post-transplant lymphoproliferative disorders (PTLD) in kidney transplant recipients from two major transplantation centers in Japan. Graft survival has improved due to a reduction in the acute rejection rate by advances in immunosuppressive agents; however long-term survival after kidney transplantation remains unchanged. Therefore, it is extremely important to focus on malignancy, especially PTLD after kidney transplantation. They emphasized the strategies to identify PTLD and suggested the benefits of positron emission tomography-computed tomography for ascertaining PTLD. They also revealed that mycophenolate mofetil contributed the onset of PTLD, and rituximab was not significantly associated with the incidence of PTLD. We have to be careful for each immunosuppressive agent. Yamashita et al. (Shizuoka, Japan) examined the incidence and location of lower extremity deep vein thrombosis (DVT) in patients undergoing RC. Venous thromboembolism (VTE) including DVT and pulmonary embolism is a serious perioperative complication in urological surgery. RC, whether open or robot-assisted surgery, is the procedure with the highest risk of perioperative VTE in urological surgery according to the European Association of Urology (EAU) guidelines on thromboprophylaxis in urological surgery. They also identified that preoperative D-dimer level was a significant risk factor for preoperative DVT, and preoperative D-dimer level, type of urinary diversion (ileal neobladder), and preoperative DVT were significant risk factors for postoperative DVT. EAU guidelines strongly recommended the use of pharmacological prophylaxis in all patients undergoing open and robot-assisted RC. These results might suggest appropriate patients for pharmacological prophylaxis in RC. Unfortunately, the limited space does not allow me to introduce all the articles. However, all the papers are very interesting and informative. Please enjoy this issue of the International Journal of Urology. None declared.

New Drugs for Bacillus Calmette Guérin-Unresponsive Nonmuscle Invasive Bladder Cancer

For intermediate- and high-risk nonmuscle invasive bladder cancer (NMIBC), intravesical Bacillus Calmette-Guérin (BCG) therapy is the standard adjuvant treatment following transurethral resection of bladder tumor. Although intravesical BCG therapy improves disease progression and bladder preservation in most patients, there are still a considerable number of BCG-unresponsive cases, for whom radical cystectomy (RC) is the recommended salvage treatment option. However, RC is associated with high morbidity and mortality rates, and alternative treatment options are needed. New approaches, such as intravesical chemotherapy, device-assisted treatments, immune checkpoint inhibitors, viral gene therapy, antibody-drug conjugates, fibroblast growth factor receptor inhibitors, and other novel agents are being investigated. This review aims to provide an overview of the recent trials for BCG-unresponsive NMIBC.

Multi-country clinical practice patterns, including use of biomarkers, among physicians\u2019 treatment of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC)

BackgroundIntravesical bacillus Calmette-Guérin (BCG) fails in a considerable proportion of non-muscle invasive bladder cancer (NMIBC) patients despite treatment per recommended protocol. This real-world study aimed to understand the current patterns of treatment and disease management for the broad BCG-unresponsive NMIBC patient population, alongside collecting sufficient data on patients who do not undergo cystectomy.MethodsThis was a multicenter, retrospective survey of physicians treating BCG-unresponsive NMIBC patients. Data were collected in eight countries – France, Germany, Spain, Italy, United Kingdom, United States, China, and Japan – between January and May 2019. The study consisted of a short online physician survey and a retrospective chart review of eligible BCG-unresponsive NMIBC patients. Physicians abstracted chart data for the last 10 (five patients in Japan) eligible BCG-unresponsive NMIBC patients meeting the inclusion criteria, and the data were analysed for all countries combined using descriptive statistics. Country-specific analyses were also carried out, as appropriate.ResultsOverall, 508 physicians participated in the study. Almost one-quarter (22.9%) of physicians’ current NMIBC patient caseload was BCG-unresponsive, whereby BCG therapy was no longer considered an option. Half of physicians (49.4%) did not regularly use biomarker tests in their practice, with particularly few physicians undertaking biomarker testing in Spain and Japan. Biomarker testing varied considerably, with the proportions of physicians selecting ‘none’ ranging from 11.4% in China to 70.3% in Japan. Physicians reported transurethral resection of the bladder tumor (TURBT) and BCG as the most common current treatments received by their patients. Chemotherapy and anti-PD-L1 treatment options were considered impactful new therapies by 94.7% and 90.0% of physicians surveyed in this study, respectively.ConclusionsThe most common treatments received by patients in this study were TURBT and BCG. Emerging new treatments are driven by exploring biomarkers, but in real-world clinical practice only half of physicians or fewer regularly tested their NMIBC patients for biomarkers; PD-1/PD-L1 was the most common biomarker test used. Most physicians reported that, in addition to chemotherapy, anti-PD-L1 was an impactful new therapy.

Positive efficacy and safety phase 3 results in both CIS and papillary cohorts BCG-unresponsive nonmuscle invasive bladder cancer (NMIBC) after IL-15RαFc superagonist N-803 (Anktiva) and BCG infusion.

431 Background: N-803, a high affinity IL-15 immunostimulatory fusion protein promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not T reg cells. Phase 1b trial demonstrated that intravesical N-803 with BCG induced complete response in all BCG-Naïve NMIBC patients, without recurrences for 24 months. An open-label, multicenter Phase 3 study (QUILT 3.032) of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825) with CIS and Papillary disease is reported. At ASCO GU 2021 we reported on CIS Cohort A and report here the full enrollment of CIS (n = 81), interim analysis of Papillary Cohort B (n = 73) and the combined efficacy and safety results in BCG unresponsive NMIBC (n = 154). Methods: All treated patients received intravesical N-803 plus BCG. The primary endpoints for papillary and CIS are disease free rate at 12 months and complete response respectively. Secondary endpoints are duration of response and cystectomy free rate. Results: Cohort A (CIS) Efficacy: Fully enrolled n = 81 with a 20.9 month median follow-up. CR rate 72% (95% CI: 60.5%, 81.1%) with median duration for 3-month responders of 24.1 months and a 60% probability of maintaining this CR for ≥ 18-months (95% CI: 43.1%, 73.5%). 12-month cystectomy free rate is 89% (95% CI: 80.1%, 94.6%), with a 100% cancer specific survival at 24-months. Cohort B (Papillary) Efficacy: To date, 73 patients have enrolled with a median follow-up of 17.3 months. The primary endpoint was met with a disease free rate at 12-months is 57% (95% CI: 43.7%, 68.5%) and at 18-months 53% (95% CI: 38.8%, 64.8%). 12-month cystectomy free rate is 95% (95% CI: 84.7%, 98.3%), with a 98% cancer specific survival at 24-months. Combined Efficacy: In the combined group (n = 154) of BCG unresponsive NMIBC, with a 19.3 months median follow-up, the 12 month cystectomy free rate was 92% (95% CI: 85.5%, 95.3%) and the 24 month OS is 94% (95% CI: 86.9%, 97.1%) with 99.5% cancer specific overall survival. Combined Safety: There were 0% treatment related SAE’s and 0% immune related SAE’s, with 4/ 154 (3%) ≥ TR Grade 3 AEs. 0% treatment related deaths have occurred as of Sept 2021 analysis date. Conclusions: N-803 and BCG was safe and well tolerated with zero percent treatment related or immune related SAEs. The primary end points of both CIS and Papillary disease were met with CR rate of 72% and 12 month Disease free rate of 57% respectively. Durable responses were noted in both cohorts and the therapy resulted in significant avoidance of cystectomy with a cystectomy free rate of 92% and a 24 month cancer specific survival of 99.5% Given the observed strong efficacy and favorable AE profile and mode of administration, N-803 represents a significant advance in the treatment option compared to existing therapies for BCG unresponsive CIS and Papillary NMIBC. Clinical trial information: NCT03022825.

Atezolizumab (atezo) with or without Bacille Calmette-Guérin (BCG) in patients (pts) with high-risk nonmuscle-invasive bladder cancer (NMIBC): Results from a phase Ib/II study.

493 Background: Standard treatment (tx) for high-risk NMIBC is transurethral resection of bladder tumor (TURBT) followed by BCG induction and maintenance. However, ≈50% of pts experience recurrence and/or progression after tx and may be ineligible for or refuse cystectomy. The PD-L1/PD-1 pathway may be involved with immune escape in NMIBC following BCG exposure. Here, we report results of atezo (anti–PD-L1) ± BCG in BCG-unresponsive, high-risk NMIBC. Methods: This multicenter study (NCT02792192) enrolled pts with BCG-unresponsive NMIBC with carcinoma in situ who had repeat TURBT. Cohort 1A and 1B pts received atezo 1200 mg IV q3w for ≤96 wk. Cohort 1B pts also received standard BCG induction (qw × 6 doses) and maintenance (qw × 3 doses at 3 mo), with optional maintenance courses at 6, 12, 18, 24, and 30 mo. For cohort 1B only, de-escalation was allowed for ≤3 BCG dose levels (full dose 50 mg, 66% and 33% of full dose). Co-primary outcomes were safety and complete response (CR) rate at 6 mo (6-mo bladder biopsy required). Duration of CR and 3-mo CR rate (key secondary outcomes) and 12-mo CR rate (exploratory) were also shown. Results: Cohorts 1A and 1B enrolled 12 pts each. Median age was 74 y; most pts had ECOG PS 0 (n = 7 [58%] in each cohort). At data cutoff (Sep 29, 2020), median atezo tx duration was 22.7 wk in cohort 1A and 31.6 wk in 1B. Following dose de-escalation in cohort 1B, the recommended BCG dose was 50 mg. BCG dose modification/interruption occurred in 4 pts (33%) due to an AE. The most common reason for tx discontinuation was disease recurrence or progression in both cohorts. Three pts (25%) in cohort 1A had atezo-related Gr 3 AEs (most common: maculopapular rash, n = 2); no atezo- or BCG-related Gr ≥3 AEs were seen in cohort 1B. Three dose-limiting toxicities occurred (1 [8%] in cohort 1A and 2 [17%] in cohort 1B), all reported as AEs of special interest. No Gr 4/5 AEs were reported. CRs, which appeared durable, were seen in both cohorts (Table). Conclusions: In this first report of atezo + BCG in NMIBC, atezo as mono- and combination therapy was well tolerated, with no new safety signals or tx-related deaths. Preliminary data suggested clinically meaningful activity, especially with atezo + BCG, requiring confirmation in a larger setting. Clinical trial information: NCT02792192. [Table: see text]

Adjuvant instillation therapy for non-muscle invasive bladder cancer - beyond BCG and mitomycin C

Due to limited local efficacy of BCG and mitomycin C and the worldwide shortage of BCG, there is a clinical need to develop novel intravesical agents and application forms in order to improve the oncological outcomes in non-muscle invasive bladder cancer (NMIBC). Gemcitabine has been investigated in various clinical trials. It has proven to be superior to BCG rechallenge and MMC in BCG-unresponsive high-risk NMIBC. GemRIS is an implantable novel form of intravesical drug delivery of gemcitabine and is currently being investigated with cetrelimab, a checkpoint inhibitor, in patients with high-risk NMIBC and MIBC. Hyperthermic intravesical chemotherapy (HIVEC) leads to increased concentrations of MMC in the bladder wall and is also being investigated in various NMIBC settings. Nadofaragene firadenovec (rAd-IFN-α/Syn3) is a recombinant adenovirus that induces release of interferon-alpha in the urothelium. In a randomised study on patients with BCG-unresponsive NMIBC, it has shown relatively superior efficacy and tolerability compared with studies evaluating the role of checkpoint inhibitor monotherapies. Opportuzumab monatox is a recombinant fusion protein which binds to EpCAM and induces release of exotoxins, resulting in cytotoxic cell death. N-803 is an interleukin (IL)-15 analogue, which has been investigated in a phase 1b study in combination with BCG and has shown durable complete response in all nine patients for 72 months. It was granted breakthrough designation status by the FDA in 2019.

Long-term efficacy of hyperthermic intravesical chemotherapy for BCG-unresponsive non-muscle invasive bladder cancer.

The recommended treatment for patients with Bacillus Calmette-Guérin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) is radical cystectomy (RC). However, many patients refuse, or are unfit for RC. Therefore, alternative bladder-sparing treatment modalities are needed for BCG-unresponsive NMIBC. In this study we sought to assess the long-term efficacy of hyperthermic intravesical chemotherapy (HIVEC) as alternative to radical cystectomy in BCG-unresponsive non-muscle invasive bladder cancer patients. Retrospectively collected data from 56 patients with BCG-unresponsive NMIBC who received ≥5 HIVEC instillations between October 2014 and March 2020 was analyzed. All patients met the BCG-unresponsive criteria according to the current EAU guideline on NMIBC 2020. Patients were followed-up with cystoscopy and/or bladder biopsies, urine cytology and annually CT-urography. The Primary outcome was the high grade (HG) recurrence-free survival (RFS), defined as the time from the first HIVEC instillation until histologically confirmed intravesical recurrence or last follow-up. The Kaplan Meier method was used to estimate survival outcomes. Secondary outcomes were: complete response rate (CR), adverse events (AE), assessed by the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) and tumor progression to muscle invasive disease or distant metastases. The median follow-up was 32.2 months (IQR 13.7-44.8). The 1- and 2-year HG-RFS was 53% (SE:6.8) and 35% (SE:6.9), respectively. The CR for patients with CIS was 70% (21/30) at 6 months. Overall, 80% of the population developed an AE, only 1 was classified as CTCAE ≥3. Limitation of this study was the small sample size. HIVEC resulted in a 2-year HG-RFS of 35% for BCG-unresponsive NMIBC patients without severe side-effects and therefore HIVEC seems to be an alternative treatment option for patients who refuse or are unfit for RC.

New Perspectives in the Medical Treatment of Non-Muscle-Invasive Bladder Cancer: Immune Checkpoint Inhibitors and Beyond.

Non-muscle-invasive bladder cancer (NMIBC) is characterized by a high rate of cure, but also by a non-negligible probability of recurrence and risk progression to muscle-invasive disease. NMIBC management requires a proper local resection and staging, followed by a risk-based treatment with intravesical agents. For many years, the current gold standard treatment for patients with intermediate or high-risk disease is transurethral resection of the bladder (TURB) followed by intravesical bacillus Calmette–Guérin (BCG) instillations. Unfortunately, in about half of high-risk patients, intravesical BCG treatment fails and NMIBC persists or recurs early. While radical cystectomy remains the gold standard for these patients, new therapeutic targets are being individuated and studied. Radical cystectomy in fact can provide an excellent long-term disease control, but can deeply interfere with quality of life. In particular, the enhanced immune checkpoints expression shown in BCG-unresponsive patients and the activity of immune checkpoints inhibitors (ICIs) in advanced bladder cancer provided the rationale for testing ICIs in NMIBC. Recently, pembrolizumab has shown promising activity in BCG-unresponsive NMIBC patients, obtaining FDA approval. Meanwhile multiple novel drugs with alternative mechanisms of action have proven to be safe and effective in NMIBC treatment and others are under investigation. The aim of this review is to analyse and describe the clinical activity of new emerging drugs in BCG-unresponsive NMIBC focusing on immunotherapy results.

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

The majority of new bladder cancer diagnoses are non-muscle invasive bladder cancer (NMIBC). For patients with intermediate-risk and high-risk NMIBC, the preferred treatment after transurethral tumor resection is bacillus Calmette-Guérin (BCG) intravesical therapy; however, some patients receiving BCG do not respond and are at risk for recurrence and progression to muscle invasive disease. Currently, there is a lack of bladder-sparing therapies for patients that do not respond to BCG therapy. This review highlights recent advances in bladder-sparing therapies for NMIBC that do not respond to BCG therapy. Several clinical trials have emerged over the past several years using novel agents. Systemic immunotherapy with pembrolizumab has shown promising activity, and recently gained FDA approval for use in BCG-unresponsive NMIBC. Gene therapy using Nadofaragene firadenovec, a replication-deficient adenoviral vector delivering interferon (IFN) alfa, shows durable results and is pending regulatory approval. Several other agents are on the horizon and there will likely be an emergence of therapies over the next several years. Patients with NMIBC that do not respond to BCG therapy are at high risk for progression to muscle invasive disease. Bladder-sparing therapeutic options for these patients are sparse but now include pembrolizumab and several other potential options are emerging. These bladder-sparing therapies will benefit patients unwilling or unable to undergo radical cystectomy.

PD09-05 PHASE 2/3 CLINICAL RESULTS OF IL-15RΑFC SUPERAGONIST N-803 WITH BCG IN BCG-UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) CARCINOMA IN-SITU (CIS) PATIENTS.

You have accessJournal of UrologyBladder Cancer: Non-invasive I (PD09)1 Sep 2021PD09-05 PHASE 2/3 CLINICAL RESULTS OF IL-15RΑFC SUPERAGONIST N-803 WITH BCG IN BCG-UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) CARCINOMA IN-SITU (CIS) PATIENTS. Karim Chamie, Sam Chang, Mark Gonzalgo, Eugene Kramolowski, Sandeep Reddy, Paul Bhar, Patrick Soon-Shiong, and Chad Garner Karim ChamieKarim Chamie More articles by this author , Sam ChangSam Chang More articles by this author , Mark GonzalgoMark Gonzalgo More articles by this author , Eugene KramolowskiEugene Kramolowski More articles by this author , Sandeep ReddySandeep Reddy More articles by this author , Paul BharPaul Bhar More articles by this author , Patrick Soon-ShiongPatrick Soon-Shiong More articles by this author , and Chad GarnerChad Garner More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001977.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Patients with NMIBC CIS unresponsive to BCG have limited treatment options. N-803 (Anktiva) is an 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 1b data in BCG-naïve 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 2/3 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 2/3 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 2/3 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. Updated data on all 80 subjects will be presented at AUA. 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. Source of Funding: ImmunityBio © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e120-e121 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Karim Chamie More articles by this author Sam Chang More articles by this author Mark Gonzalgo More articles by this author Eugene Kramolowski More articles by this author Sandeep Reddy More articles by this author Paul Bhar More articles by this author Patrick Soon-Shiong More articles by this author Chad Garner More articles by this author Expand All Advertisement Loading ...

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)