High-grade Non-muscle Invasive Bladder Cancer Research Articles

A 78-Year Old Urothelial Cancer Patient with Faster Recovery from COVID-19: Potential Benefit from Adjuvant Active Immunotherapy

A 78-year old male patient under active immunotherapy for high-grade non-muscle invasive bladder cancer presented severe COVID-19 A shorter hospitalization per

Survival Outcomes of Early versus Deferred Cystectomy for High-Grade Non-Muscle-Invasive Bladder Cancer: A Systematic Review

Background: Studies report that survival outcomes in patients with non-muscle-invasive bladder cancer (NMIBC) are worse when cystectomy is delayed. However, no systematic evidence is available. Objective: The aim of this study was to systematically review the literature to compare the long-term survival outcomes of patients with high-grade NMIBC (T1G3, including carcinoma in situ) who have early cystectomy compared to deferred radical cystectomy post-diagnosis. Materials and Methods: A systematic review was carried out by searching MEDLINE and related databases (Google Scholar, National Health Service Evidence) for all relevant studies published from 1946 to present. Additional studies were identified through following the references of relevant papers. Studies were included if they met the following criteria: inclusion of at least 30 patients having high-grade NMIBC, 2 groups treated with either early or deferred cystectomy with a clear temporal cut-off between groups and reported data on survival rate of at least 5 years. Results: Literature was systematically reviewed, and 10 studies were included, totaling 1,516 patients who underwent either primary cystectomy or deferred cystectomy. It was found that patients who underwent early cystectomy show improved 5- to 10-year cancer-specific survival (relative risk = 0.81, p = 0.029) suggesting a significant survival benefit when compared to deferred cystectomy. Conclusions: This study provides systematically gathered evidence showing benefit of early cystectomy. Despite this result, radical cystectomy greatly impairs quality of life and represents overtreatment for a significant minority. This result highlights the importance of a decisive treatment plan to minimize treatment delay.

Oncotherad immunotherapy elicits promising responses in Bacillus Calmette-Guérin-unresponsive non–muscle invasive bladder cancer: Results from phase I/ II study.

e17048 Background: Standard treatment for high-grade non-muscle-invasive bladder cancer (HGNMIBC) is transurethral resection of the bladder tumor followed by intravesical Bacillus Calmette-Guérin (BCG) immunotherapy. Up to 40% of patients with HGNMIBC will fail intravesical BCG therapy. A promising therapeutic perspective is represented by OncoTherad immunotherapy. OncoTherad is a nanostructured inorganic phosphate complex associated to glycosidic protein developed by University of Campinas/Brazil that exhibits antitumor properties. The aims of this study were to evaluate the efficacy and safety of OncoTherad immunotherapy for BCG-refractory or relapsed HGNMIBC. Methods: We conducted a prospective, single-center (Municipal Hospital of Paulinia, São Paulo, Brazil), single-arm phase I/ II study of OncoTherad immunotherapy in 29 (18 male, 11 female) patients with BCG-unresponsive HGNMIBC (≥ 1 previous course of BCG intravesical therapy). The schedule was initiated with weekly intravesical (120 mg/mL) and intramuscular (25 mg/mL) OncoTherad treatment for 6 weeks, followed by one every other week application for 3 months and, one monthly application until the end of the treatment (24 months). Follow-up was performed with systematic mapping biopsies of the bladder, cystoscopy and ultrasound. The primary endpoint was pathological complete response (pCR) and recurrence-free survival (RFS). The recurrence was defined as histology proven tumor recurrence (any grade) and monitored at 3-month intervals. Secondary endpoints were time to disease recurrence and safety response. Results: The median age of the 29 patients was 64 years (range 34-94). At baseline pTis, pTaG2-3, pT1G2-3 occurred in 10%, 59% and 31% of patients respectively. OncoTherad treatment showed pCR rates (95% CI) of 100% at 3, 6 and 9 months, 89,6% (26/29) at 12 months and, 89,6% (26/29) at 24 months. A 24-months RFS rate in all patients was 79,3%. Also, the median time to disease recurrence for patients was 459 days (15,3 months; 95% CI) at 24-months follow-up. 95% of adverse events were Grade 1 or 2. The most commonly reported treatment-related adverse events were dysuria (51,7%), cystitis (34,5%), pruritus (44,8%), rash (27,6%), arthralgia (27,6%) and fatigue (27,6%). Conclusions: In conclusion, OncoTherad seems a safe and effective treatment option for BCG-unresponsive HGNMIBC patients and may provide benefit for preventing tumor recurrence. Clinical trial information: RBR-6swqd2.

Treatment of High-grade Non–muscle-invasive Bladder Carcinoma by Standard Number and Dose of BCG Instillations Versus Reduced Number and Standard Dose of BCG Instillations: Results of the European Association of Urology Research Foundation Randomised Phase III Clinical Trial “NIMBUS”

BackgroundIntravesical instillation of bacillus Calmette-Guérin (BCG) is an accepted strategy to prevent recurrence of non–muscle-invasive bladder cancer (NMIBC) but associated with significant toxicity. ObjectiveNIMBUS assessed whether a reduced number of standard-dose BCG instillations are noninferior to the standard number and dose in patients with high-grade NMIBC. Design, setting, and participantsA total of 345 patients from 51 sites were randomised between December 2013 and July 2019. We report results after a data review and safety analysis by the Independent Data Monitoring Committee based on the cut-off date of July 1, 2019. InterventionThe standard BCG schedule was 6 wk of induction followed by 3 wk of maintenance at 3, 6, and 12 mo (15 instillations). The reduced frequency BCG schedule was induction at wks 1, 2, and 6 followed by 2 wk (wks 1 and 3) of maintenance at 3, 6, and 12 mo (nine instillations). Outcome measurements and statistical analysisThe primary endpoint was time to first recurrence. Secondary endpoints included progression to ≥ T2 and toxicity. Results and limitationsIn total, 170 patients were randomised to reduced frequency and 175 to standard BCG. Prognostic factors at initial resection were as follows: Ta/T1: 46/54%; primary/recurrent: 92/8%; single/multiple: 57/43%; and concomitant carcinoma in situ: 27%. After 12 mo of median follow-up, the intention-to-treat analysis showed a safety-relevant difference in recurrences between treatment arms: 46/170 (reduced frequency) versus 21/175 patients (standard). Additional safety analyses showed a hazard ratio of 0.40 with the upper part of the one-sided 97.5% confidence interval of 0.68, meeting a predefined stopping criterion for inferiority. ConclusionsThe reduced frequency schedule was inferior to the standard schedule regarding the time to first recurrence. Further recruitment of patients was stopped immediately to avoid harm in the reduced frequency BCG arm. Patient summaryAfter surgical removal of the tumour, patients with high-grade non–muscle-invasive bladder cancer are treated with bacillus Calmette-Guérin to prevent recurrence and progression. This is associated with significant side effects. We report the results of a clinical trial showing a reduction in the number of instillations (from 15 to nine in total) being inferior to the standard protocol. From today’s perspective, complete tumour resection and a standard number of instillations remain the standard of care.

PCN42 TREATMENT PATTERNS AND SURVIVAL AMONG PATIENTS WITH BCG UNRESPONSIVE HIGH-GRADE NON-MUSCLE INVASIVE BLADDER CANCER: AN ASSESSMENT OF THE SEER-MEDICARE DATA

Standard treatment options are limited for patients with high-grade (HG) non-muscle invasive bladder cancer (NMIBC) after adequate Bacillus Calmette-Guérin (BCG) therapy. We examined the real-world treatment patterns and survival among BCG unresponsive patients diagnosed with HG NMIBC in the US. Using SEER-Medicare database (2008-2015), we identified BCG unresponsive patients among those who received adequate BCG (≥7 instillations within 9 months of diagnosis) based on the initiation of additional therapy within 12 months of the last consecutive BCG instillation. Therapies evaluated post BCG were radical cystectomy and bladder-preserving treatments (BPTs) (thiotepa, valrubicin, gemcitabine, mitomycin C, docetaxel, nab-paclitaxel, any combinations of these, chemo-radiation, and BCG + interferon alpha). Overall survival (OS) and bladder cancer-specific survival (BCSS) were assessed using Kaplan-Meier analysis and Cox proportional hazards models. Among the 16,837 patients with HG NMIBC, only 13.9% received adequate BCG. Of these, 16.2% (378 patients) were BCG unresponsive and formed the study sample. Only 15.1% of these patients received radical cystectomy as their first treatment post-BCG. Of the 84.9% undergoing BPT, the most commonly used agents were mitomycin C (55.1%), BCG + interferon alpha (17.8%), valrubicin (11.8%), and gemcitabine (7.5%). The 5-year OS was similar between the two groups (52.6% vs. 51.6%) but patients receiving radical cystectomy had a lower 5-year BCSS (67.4% vs. 79.6%). After adjusting for potential confounders, patients receiving radical cystectomy had a significantly higher hazard of bladder cancer mortality (HR 2.09; 95% CI 1.05-4.13). BCG was underutilized in patients with HG NMIBC, indicating substantial unmet needs. The proportion of patients receiving radical cystectomy among BCG unresponsive patients was also low. Patients who received BPTs had similar OS as those who underwent radical cystectomy, but had a lower risk of bladder-cancer specific mortality. Further research is warranted to inform the contemporary treatment patterns and outcomes of this difficult-to-treat patient population.

PCN62 DISEASE BURDEN ASSOCIATED WITH PROGRESSION IN PATIENTS WITH HIGH-GRADE NON-MUSCLE INVASIVE BLADDER CANCER RECEIVING BLADDER PRESERVING THERAPIES AFTER ADEQUATE BCG INDUCTION: A SEER-MEDICARE DATABASE STUDY

Patients with high-grade (HG) non-muscle invasive bladder cancer (NMIBC) have limited treatment options after adequate Bacillus Calmette-Guérin (BCG) therapy. Many eventually progress to muscle-invasive bladder cancer (MIBC). This study assessed the disease burden of progression among HG NMIBC patients initiating bladder preserving therapies (BPT) after adequate BCG induction.

PD12-07 A PHASE III STUDY TO EVALUATE THE SAFETY AND EFFICACY OF INTRAVESICAL NADOFARAGENE FIRADENOVEC FOR PATIENTS WITH HIGH-GRADE, BCG UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER

INTRODUCTION AND OBJECTIVE: A subset of patients (pts) with high-grade non-muscle invasive bladder cancer (NMIBC) who are treated with BCG will have BCG unresponsive disease, and are at considerable risk for tumor recurrence and progression. The development of effective intravesical therapies represents an important unmet need in this population. Nadofaragene firadenovec is a novel intravesical gene-mediated therapy that delivers the human IFNα2b gene resulting in sustained IFNα2b expression, and provided durable responses in a previous Phase 2 trial. Herein, we report results from the papillary disease (PD) cohort of the Phase 3 trial. METHODS: This multicenter, open-label Phase 3 study investigated nadofaragene for high-grade NMIBC (carcinoma in situ [CIS ± Ta/T1], or PD [Ta/T1 alone]) unresponsive to BCG. Nadofaragene (3X1011 vp/mL [75 mL]) was administered intravesically once every 3 months for up 4 doses in the initial 12 months. Pts with no evidence of high-grade disease at month 12 were offered continued treatment at the investigator’s discretion. The primary endpoint was complete response (CR) rate at any time in the CIS cohort (results presented in a prior abstract). Secondary end points included rate and durability of high-grade-recurrence-free (HGRF) survival as well as safety in PD pts, reported herein. RESULTS: A total of 157 pts were enrolled, of whom 50 were in the PD cohort (safety population n=50; efficacy population n=48). At study entry, all pts were BCG-unresponsive. Of the 48 pts in the efficacy population, 35 (72.9%), 30 (62.5%), 28 (58.3%), and 21 (43.8%) achieved HGRF survival at months 3, 6, 9, and 12, respectively. Within this PD cohort, the most common treatment-emergent adverse events (TEAEs) were transient in nature; specifically, instillation site discharge 30%; bladder spasm 18%; micturition urgency 18%; urinary tract infection 18%. The most common drug-related TEAEs were instillation site discharge 26%; bladder spasm 14%; micturition urgency 14%; dysuria 14%. Grade 3 TEAEs were reported in 9 pts (3 study drug-related), with a single Grade 4 (not related to study drug). No pt had an adverse event leading to death. CONCLUSIONS: Nadofaregene firadenovec was well tolerated and achieved an encouraging, durable HGRF survival in high-grade BCG-unresponsive NMIBC pts with PD. This demonstrates a clinically meaningful benefit in a pt population for whom to date non-surgical treatment options have remained limited. Clinical trial information: NCT02773849. Source of Funding: FKD

PD12-09 INHERITED CANCER PREDISPOSITION GENE VARIANTS IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER

INTRODUCTION AND OBJECTIVE: Emerging data have shown that patients with locally advanced and metastatic urothelial cancer frequently harbor rare germline variants in cancer predisposition genes, particularly in DNA damage response (DDR) genes. The prevalence of such rare germline variants in patients with non-muscle invasive bladder cancer (NMIBC), the most common form of urothelial cancer, has not been thoroughly studied. METHODS: Patients with NMIBC who were unselected for inherited cancer syndromes were prospectively enrolled in a protocol for molecular profiling of tumor-normal DNA pairs using next-generation sequencing within a CLIA-certified lab (NCT01775072). Germline variation analysis was performed on a clinically annotated cohort of 100 patients with NMIBC that we had previously reported on their somatic mutational spectrum (Pietzak et al Eur Urol 2017). Pathogenic or likely pathogenic (P/LP) germline variants in a panel of 82 genes associated with hereditary cancer predisposition were assessed in accordance with recommendations of the American College of Medical Genetics and Genomics. RESULTS: We identified P/LP germline variants in 12 (15.7%) patients with high-grade NMIBC (n = 76) and 0 patients with low-grade NMIBC (n = 24). Nine (11.8%) patients with high-grade NMIBC had P/LP variants in DDR genes; four were in nucleotide excision repair genes (ERCC2 [2] and ERCC3 [2]) and four were in homologous recombination repair genes (BRCA1 [1], BARD1 [1], RAD50 [1], and RECQL4 [1]). An additional patient had a P/LP germline mutation SDHA and two others had P/LP low-penetrance germline mutations in FH and APC. Interestingly, no patient with a germline mutation had early-onset disease (≤ 45 years at diagnosis) or a family history of urothelial cancer. Compared to patients with high-grade NMIBC without germline variants, those with P/LP germline variants had a higher frequency of nonurothelial cancers (15% vs 42%), Ashkenazi Jewish ancestry (27% vs 42%), and multifocal tumors at initial diagnosis (42% vs 75%). Correlation of P/LP variants with clinical outcomes in a larger cohort is ongoing and is expected to be available for presentation at the meeting. CONCLUSIONS: Our findings suggest that genetic predisposition may play a larger role than expected in NMIBC, as P/LP germline variants were seen in 16% of patients with high-grade NMIBC. If validated, these results may have profound implications for genetic counseling, screening, and prevention. The prevalence of germline DDR variants, which may increase susceptibility to bladder cancer, suggests that therapeutic strategies exploiting tumor vulnerabilities due to impaired DNA repair warrant further investigation in high-grade NMIBC. Source of Funding: This work was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers, the Michael and Zena Wiener for Therapeutics Program in Bladder Cancer, Pin Down Bladder Cancer, Cycle for Survival, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, NIH/NCATS Grant Number UL1-TR002384, the National Cancer Institute Cancer Center Core Grant Number P30-CA008748, MSKCC SPORE in Bladder Cancer P50-CA221745, NIH/NCI K12 Paul Calabresi Career Development Award for Clinical Oncology (K12 CA184746)

PD12-12 PATIENT MATCHED GENOMIC ANALYSIS OF HIGH-GRADE NON-MUSCLE INVASIVE BLADDER CANCER SPECIMENS PRE- AND POST-BCG IMMUNOTHERAPY

INTRODUCTION AND OBJECTIVE: High-grade non-muscle invasive bladder cancer (NMIBC) is treated with intravesical BCG immunotherapy. Unfortunately, 40% of patients develop recurrence with a subset progressing. Identification of genomic alterations associated with response to BCG could identify novel approaches to prevent or delay recurrence. To explore tumor evolution under the selective pressure of BCG therapy, we utilized targeted exon capture sequencing (IMPACT) to compare tumor collected pre- and post-BCG treatment. METHODS: High-grade NMIBC patients treated with BCG had IMPACT performed on pre- and post-treatment tumor. Patients were classified as having BCG unresponsive or late-relapsing disease. BCG unresponsive tumors were those with recurrent high-grade disease within 12 months after completion of adequate BCG. BCG late-relapsing tumors were those with high-grade recurrence over 12 months after BCG treatment. The association between patient characteristics, genomic profiles and tumor mutational burden (TMB) with high-grade recurrence following BCG was estimated. TMP pre- and post-treatment was compared using a paired Wilcoxon test. RESULTS: Matched specimens from 18 patients were analyzed. The median age at diagnosis was 60 years (IQR 50-75) and 15 (83%) were male. 11 patients (61%) were cTa, 6 (33%) cT1 and 1 cTis. The mutational concordance between pretreatment and posttreatment BCG specimens was 80% (IQR 65-96) (Figure 1). TMB between matched specimens was not significantly different with median 7 in both (p=0.88). Notably three patients gained a potentially actionable mutation post-BCG like patient 10 with a gain of a FGFR3 mutation after FACETS analysis. Univariable analysis did not detect statistically significant differences in BCG-unresponsive vs late-relapsing with respect to age, gender, number of tumors, smoker, tumor size or cT-stage. Comparing genomic alterations, a significant difference in the present of a CREBBP mutation was detected between these two cohorts (p=0.03). As a chromatin modifying gene, mutations in CREBBP may potentially be actionable with histone deacetylase inhibitors. CONCLUSIONS: With recurrent BCG shortages, further knowledge of resistance patterns can help guide clinical practice. We found a high concordance between tumor pre- and post-BCG treatment. The cohort identified here was small but there were some notable differences between pre- and post-treatment specimens, especially with gain of actionable mutations in post-BCG specimens. While we examined only patients with BCG recurrences, there were a number of actionable mutations that could serve as potential targets for novel therapies.Source of Funding: This work was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers, the Michael and Zena Wiener for Therapeutics Program in Bladder Cancer, Pin Down Bladder Cancer, Cycle for Survival, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, NIH/NCATS Grant Number UL1-TR002384, the National Cancer Institute Cancer Center Core Grant Number P30-CA008748 and by SPORE in Bladder Cancer P50-CA221745.

MP61-13 DO URINARY-BASED MOLECULAR BIOMARKER HAVE THE ABILITY TO PREDICT THE GRADE OF NON-MUSCLE INVASIVE BLADDER CANCER GRADE?

INTRODUCTION AND OBJECTIVE: Micro-RNA155 (mir-155), MicroRNA-200b (mir-200b), human telomerase reverse transcriptase (hTERT), and E2F3 transcription factor had a role in bladder cancer pathogenesis. We aim to assess their role in diagnosis the non-muscle invasive bladder cancer (NMIBC) grade compared to histopathological results. METHODS: A registered prospective trial (NCT03591367) for 64 NMIBC patients. From voided urine samples, total RNA extract from sedimented urothelial cells were analysed by a reverse transcriptase-polymerase chain reaction assay for the presence of mir-155, mir-200b, hTERT and E2F3 transcript. A receiver operating characteristics (ROC) was plotted in order to choose the best cut-off point. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for each test. RESULTS: Patients demographic were comparable (table 1). The expression levels of the mir-155 didn’t show difference between high grade (HG) and low grade (LG) (p=0.06) (table 1). Both mir-155 and mir-200b had the lowest AUC (table 2). E2F3 and hTERT expression in urine was higher in HG NMIBC group than in LG NMIBC (P < 0.001) (table 1). The sensitivity, specificity, accuracy of E2F3 were 86%, 76.2%, and 82.8%, respectively. The sensitivity, specificity, accuracy of hTERT were 86%, 66.7%, and 79.7%, respectively (table 2 and figure 1). CONCLUSIONS: As molecular urinary biomarkers; E2F3 and hTERT have the highest potential for prediction of the grade of NMIBC to either low or high grade.Source of Funding: No

Disease progression among patients who receive available bladder preservation therapies after failure of BCG therapy in the SEER-Medicare data.

453 Background: For patients with high-grade (HG) non-muscle invasive bladder cancer (NMIBC) who recur after Bacillus Calmette-Guérin (BCG) therapy, treatment options other than radical cystectomy have been limited. This study examined real-world utilization and outcomes of current bladder preservation therapies (BPT) after BCG treatment. Methods: We analyzed the SEER-Medicare database and identified patients diagnosed with HG NMIBC between 2008 and 2015 who received at least one BCG induction course (defined as ≥5 weekly instillations). Use of BPT within six months of the last consecutive BCG instillation was identified and included BCG + interferon alpha, docetaxel, doxorubicin, epirubicin, gemcitabine, mitomycin C, nab-paclitaxel, thiotepa, valrubicin, or their combinations. Progression was identified as initiation of treatment for muscle-invasive bladder cancer, radical cystectomy, or presence of metastases. Time to progression (TTP) was defined as time from BPT initiation to progression event. Progression-free survival (PFS) was assessed from BPT initiation and defined as the absence of progression or death due to bladder cancer. TTP and PFS were assessed using Kaplan-Meier analysis. Results: A total of 7,074 patients were diagnosed with HG NMIBC and received ≥ 5 BCG weekly induction instillations. Of these, 8.8% (620 patients) initiated BPT. The most commonly used agents were mitomycin C (66.0%), followed by BCG + interferon alpha (22.9%), valrubicin (4.0%), doxorubicin (2.9%), and gemcitabine (2.1%). Disease progression occurred in 18.7% of patients within 1 year of treatment initiation (40.5% due to metastases), 36.4% within 3 years (50.0% due to metastases), and 45.4% within 5 years (50.2% due to metastases). The rate of PFS was 80.9%, 61.8%, and 52.3% at 1, 3, and 5 years, respectively. Conclusions: High rates of metastatic disease are noted in HG NMIBC following available BPT treatments after failure of BCG therapy. A high unmet need remains for novel bladder-sparing therapies to improve outcomes in this difficult-to-treat population.

Comprehensive targeted gene profiling to determine the genomic signature likely to drive progression of high-grade nonmuscle invasive bladder cancer to muscle invasive bladder cancer.

568 Background: Bladder cancer is the fifth most common cancer and eighth leading cause of cancer related-death in North America. It can present as non-muscle invasive bladder cancer (NMIBC) and/or muscle invasive bladder (MIBC). Although genomic profiling studies have established that low-grade NMIBC and MIBC are genetically distinct, high-grade NMIBC can recur and progress to MIBC [ Knowles, M.A. and C.D. Hurst, 2015]. Low grade, non-invasive bladder cancers are characterized by activating mutations in fibroblast growth factor receptor 3 (FGFR3), HRAS or other pathways of receptor kinase activation. High-grade disease, which is often becomes invasive, is characterized by inactivation of TP53 and Rb pathways [Kim, J., et al.]. Finding a subtype of invasive carcinoma with FGFR3 mutation may suggest an alternate pathway by which low grade, non-invasive pathology could transform into invasive disease [Knowles, M.A. and C.D. Hurst, 2015]. Methods: In this study, using a total of 30 bladder cancer (NMIBC and MIBC) patient samples from Windsor Regional Hospital Cancer Program, we performed comprehensive targeted gene sequencing to identify single nucleotide variants, small insertions / deletions, copy number variants and splice variants in over 500 common tumor genes panel. Results: Preliminary data from our study correlates with previously published mutation landscape for NMIBC and MIBC, and includes mutations in EGFR, FGFR3, FGFR4, PIK3CA, CDK6, ALK, JAK, as well as RET. While mutations in AKT1, BRCA1, CCND1, ERBB2, FGFR1, FGFR2, HRAS, and MET appear to be prevalent in NMIBC, mutations in IDH1 and MAP2K2 appear to be more common in MIBC. Three of the samples used in the study are from patients who progressed from high-grade NMIBC to MIBC. Conclusions: Therefore, have the genomic profiling performed at these two stages, which provides a unique ability to identify the potential “genomic triggers” for the transition.

Marker lesion study of oral FGFR inhibitor BGJ398 in patients with FGFR3-altered intermediate-risk nonmuscle-invasive bladder cancer.

510 Background: FGFR3 alterations are prevalent in non-muscle-invasive bladder cancer (NMIBC). We conducted a marker lesion study of the oral FGFR inhibitor BGJ398 in patients with intermediate-risk NMIBC. Methods: Patients with recurrent clinical high-grade papillary NMIBC following intravesical BCG were eligible. FGFR3 alteration status was determined via testing of pre-treatment or archival tumor tissue. BGJ398 was administered at 125 mg PO daily for a 3 week on, 1 week off schedule (1 cycle). Response was determined after 2 cycles (at 7 weeks). Patients with a complete response (CR) had the option to continue therapy. Results: We enrolled four patients on trial, which we closed secondary to low accrual. Three patients had a CR at the 7-week evaluation. The other patient had a smaller, necrotic lesion after prematurely discontinuing treatment at 4 weeks. Clinically significant toxicities included eye disorders, skin and nail disorders, and elevations in LFTs. Two patients required dose reductions for toxicities. Two patients discontinued treatment before the 7-week evaluation, one for Grade 2 skin toxicity and the other for Grade 3 LFT elevation. All other toxicities were Grades 1 and 2. The other two patients continued treatment beyond a CR at 7 weeks but stopped after 3 and 4 cycles (after 11 and 16 weeks) for vision/skin toxicities and nail infection/mucositis, respectively. Conclusions: The oral FGFR inhibitor BGJ398 showed antitumor activity in a marker lesion study of patients with recurrent high-grade papillary NMIBC. Treatment was discontinued secondary to toxicities in all subjects, after a range of 4 to 16 weeks. Further investigation may be warranted for lower doses of oral BGJ398 or other formulations, such as intravesical delivery. Clinical trial information: NCT02657486. [Table: see text]

Treatment of high-grade non-muscle invasive bladder carcinoma by standard number and dose of BCG instillations versus reduced number and standard dose of BCG instillations: Results of the phase III clinical trial (NIMBUS).

436 Background: Intravesical instillation of BCG is an accepted strategy to prevent recurrence of non muscle invasive bladder cancer (NMIBC). However, the optimal number of instillations is unknown. NIMBUS assessed whether a reduced number/standard dose BCG instillations is not inferior to standard number and dose BCG in patients with high-grade (HG) NMIBC. The primary endpoint was time to first recurrence. Methods: The aim was to enroll 824 BCG naïve patients with HG Ta-T1 NMIBC +/- CIS. NIMBUS was an international randomized not blinded trial to establish therapeutic equivalence defined as the lower part of the Confidence Interval (CI) (using one-sided 2.5% level of significance) being higher than a HR (hazard experimental/hazard standard) of 0.75 for recurrence. The treatment arms were: Standard: Induction cycle BCG weekly wks 1-6; maintenance cycles at months 3,6,12 (wks 1,2,3) and Reduced: Induction cycle at wks 1,2,6; maintenance cycles at months 3,6,12 (wks 1,3). Safety was evaluated at yearly intervals by the IDMC and in case inferiority was shown, defined as the upper part of the CI (one-sided 2.5% level) lower than a HR of 0.75, an advice to stop the trial would be given. Results: Available data at July 1, 2019 were analyzed for the IDMC meeting. A total of 345 patients were recruited from Germany (149), the Netherlands (109), France (64), Belgium (22) and Spain (1). Prognostic factors at initial resection were Ta/T1: 46/54%; primary/recurrent disease: 92/8%; single/multiple lesions: 57/43% and concomitant CIS/no CIS: 27/73%. The intention to treat analysis showed a clear difference in time to and number of recurrences between treatment arms: 27% in the reduced arm versus 12% in the standard arm. Known prognostic factors were evenly distributed between arms. Additional safety analyses were performed showing a HR of 0.40 [95% CI: 0.24-0.67]. Conclusions: Safety analysis showed that the reduced frequency schedule of BCG was inferior to the standard frequency schedule for time to first recurrence according to the previously defined stop criterion. Recruitment of patients was stopped immediately. Clinical trial information: NTR4011.

Safety and efficacy of intravesical nadofaragene firadenovec for patients with high-grade, BCG unresponsive nonmuscle invasive bladder cancer (NMIBC): Results from a phase III trial.

442 Background: Patients (pts) with BCG-unresponsive NMIBC are at significant risk for disease recurrence and progression. While cystectomy can be curative, many such pts are unwilling or unable given the attendant morbidity of surgery. To date, effective salvage intravesical therapies in this setting remain lacking. Nadofaragene firadenovec is a novel intravesical gene-mediated therapy that delivers the human IFNα2b gene resulting in IFNα2b expression that provided durable responses in a previous Phase 2 trial. Herein, we report the results from a follow-up Phase III trial of this agent for pts with BCG unresponsive NMIBC. Methods: This multicenter, open-label Phase 3 study investigated nadofaragene for high-grade NMIBC (CIS ± Ta/T1, or Ta/T1 alone) unresponsive to BCG. Nadofaragene (3X1011 vp/mL [75 mL]) was administered once every 3 months for up 4 doses in the initial 12 months, with additional dosing at the investigator’s discretion. The primary endpoint was complete response (CR) at any time in pts with carcinoma in situ (CIS). Results: A total of 157 pts (safety population, n=157; efficacy population, n=151) were enrolled. Among pts with CIS (n=103), 55 (53.4%) (95% CI, 43.3-63.3) achieved CR, all by month 3 after treatment. Of these 55 CIS CR pts, 25 (45.5%) remained free of high-grade recurrence at month 12, confirmed on protocol-mandated biopsy. For pts with HG Ta/T1 alone, 35 (72.9%) and 21 (43.8%) were free from recurrence at 3 and 12mos, respectively. Most treatment-emergent adverse events (TEAEs) were transient in nature: instillation site discharge 33.1%; fatigue 23.6%; bladder spasm 19.7%; micturition urgency 17.8%; hematuria 16.6%. There were 2 Gr4 TEAEs (sepsis and anaphylactic reaction, neither related to study drug) and no Gr5 TEAEs. Conclusions: Nadofaragene achieved CR in 53.4% of pts with BCG-unresponsive CIS, and was well tolerated. Responses were noted early and remained durable to one year. These data represent a potentially significant management advancement for a historically difficult to treat disease state. Clinical trial information: NCT02773849.

Bacillus Calmette-Guérin immunotherapy for bladder cancer: a review of immunological aspects, clinical effects and BCG infections.

Bacillus Calmette-Guérin (BCG) immunotherapy for bladder cancer has been used since 1976 when the first evidence of its ability to lower recurrence and progression rates was published. Today, BCG immunotherapy is the choice of care for high-grade non-muscle invasive bladder cancer (NMIBC) after transurethral resection. This article presents indications and procedure of BCG instillations, and outlines the effects on recurrence and progression of NMIBC. The BCG-induced immunity in NMIBC is not yet fully understood. Animal studies point towards BCG inducing specific tumour immunity. We describe the current knowledge of how this immunity is induced, from internalization of BCG bacilli in urothelial cells, to cytokine- and chemokine-mediated recruitment of neutrophils, monocytes, macrophages, T cells, B cells and natural killer cells. In addition, we describe the process of trained immunity, the non-specific protective effects of BCG. Recent studies also indicate that dysbiosis of the urinary microbiome may cause lower urinary tract dysfunction. Side effects of BCG bladder instillations range from common, mild and transient symptoms, such as dysuria and flu-like symptoms, to more severe and rarely occurring life-threatening complications. We review the literature and give an overview of reported incidences and management of BCG infections after intravesical instillation.

How well do we manage non-muscle invasive bladder tumors? A UK audit of real-life practices.

The aim of this study was to assess the quality of TURBT (transurethral resection of bladder tumor) using surrogate parameters and evaluate adherence to the guidelines regarding the management of bladder tumors. A clinical audit of all new diagnosis of bladder cancer was undertaken from January 2016 to January 2017. A total of 101 new bladder cancer cases were included. Surrogates of TURBT quality including presence of detrusor in the specimen, rate of re-TUR, presence of carcinoma in situ, and 3-month recurrence rates were analyzed. Adherence to guidelines regarding management of non-muscle invasive bladder cancer including time to re-TUR and utilization of single instillation chemotherapy was evaluated. Absence of detrusor muscle in the specimen of the initial TURBT was noted in 22.8% of the cases. The chance of including muscle in the specimen was almost four-fold for tumors larger than 3 cm. A single instillation of intravesical chemotherapy following TURBT was administered in only 40% of eligible patients; 54.3% of patients had a re-TUR, the majority (61.3%) for high-grade non-muscle invasive bladder cancer on initial TURBT. Re-TUR was done on average 10 weeks after initial TURBT. The 3-month recurrence rate was 36.0% with larger tumors (>3 cm) being more prone to early recurrences. Early recurrences were not affected by intravesical instillations with bacillus Calmette-Guérin or mitomycin C although there was a positive association between the presence of carcinoma in situ on initial resection and early recurrences. One in two patients will have a re-TUR, and approximately one in two patients will have tumor on re-TUR. Single immediate chemotherapy instillations after TURBT are underutilized. The presence of carcinoma in situ on initial TURBT and tumor size were predictors of early recurrences.

Prognostic significance of pre- and post-treatment PD-L1 expression in patients with primary high-grade non-muscle-invasive bladder cancer treated with BCG immunotherapy.

Programmed cell death-1 ligand-1 (PD-L1) expression has been associated with prognostic implications in urologic malignancies. We aimed to investigate prognostic significance of pre- and post-treatment PD-L1 expression in patients treated with BCG for high-grade non-muscle-invasive bladder cancer (NMIBC). We reviewed a total of 141 high-grade NMIBC cases treated with transurethral resection + ≥ 6 BCG instillations between 2004 and 2017. PD-L1 immunohistochemistry (IHC) scoring was done on 0-3 scale, and cut-off for positive and high-level PD-L1 expression was set to ≥ 1% and ≥ 5% staining of tumor-infiltrating immune cells (IC), respectively. Clinicopathologic characteristics and oncologic outcomes [recurrence-free (RFS) and progression-free survival (PFS)] were compared, stratified by PD-L1 positivity. The prognostic role of PD-L1 was assessed using Kaplan-Meier, and univariate and multivariate Cox regression analyses. Pre-treatment, 46.2% and 6.8% of high-grade NMIBC demonstrated positive and high-level PD-L1 expression, respectively. Positive PD-L1 expression was associated with submucosal invasion and refractory-tumor recurrence. PD-L1 expression was not associated with RFS or PFS in regression analysis. Post-treatment, 55.1% and 11.6% of recurrent tumors demonstrated positive and high-level PD-L1 expression, respectively. Down-regulation of PD-L1 expression was noted in patients with refractory recurrence (p = 0.012). Pre-treatment PD-L1 expression was associated with unfavorable pathological features in primary high-grade NMIBC and its expression level after BCG immunotherapy was significantly decreased in patients with refractory recurrence. PD-L1 expression did not have prognostic value for PFS or RFS; therefore, further research is necessary to identify novel biomarkers for prediction of disease outcomes in high-grade NMIBC.

Early recurrence and the need for re-resection following Photodynamic diagnosis–assisted Transurethral Resection of Bladder Tumours: Multi-centre real-world experience of the UK PDD Users Group

Objective: This study aimed to investigate the association between Photodynamic Diagnosis (PDD) with hexaminolevulinate (HAL) and the rate of complete resection and disease persistence at first follow-up cystoscopy for non-muscle-invasive bladder cancer (NMIBC) in UK real-world practice. Methods: Audit data were pooled from six UK centres where HAL PDD was used in patients with a new NMIBC diagnosis undergoing transurethral resection of bladder tumours (TURBT) since 2008. Patients received adjunctive intra-vesical therapy and surveillance in line with European and UK guidelines, including early re-resection in high-grade NMIBC. Results: PDD-assisted TURBT was done in 837 patients with new NMIBC. The detrusor muscle was present in 69.4% of cases. At early re-TURBT in 207 high-risk patients, 13.0% had residual disease. Multifocal disease was the most significant factor in increasing the rate of residual disease (odds ratio excluding cases of CIS=4.1; 95% confidence interval 1.5–11.3). The recurrence rate at first follow-up cystoscopy (RRFFC) was 10.6% (8.9% in patients with complete initial TURBT). In the historical cohort undergoing good-quality white-light TURBT, RRFFC was 31%; 40.5% of high-risk patients had residual disease at early re-TURBT. Conclusion: HAL PDD may increase the rates of complete resection, reducing the risk of early recurrence and the need for routine re-resection in high-grade NMIBC. Level of evidence: 2b.

Bacillus Calmette-Guérin (BCG) and Gemcitabine in People With High-Grade Non-Muscle Invasive Bladder Cancer That Came Back After BCG Treatment

Bacillus Calmette-Guérin (BCG) and Gemcitabine in People With High-Grade Non-Muscle Invasive Bladder Cancer That Came Back After BCG Treatment