This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada. Key Words Competing Interests Article Information Bacillus Calmete-Guerin, BCG, BCG- unresponsive, BCG refractory, BCG relapsing, bladder cancer None declared. Received on May 21, 2022 Accepted on July 27, 2022 This article has been peer reviewed. Soc Int Urol J. 2022;3(5):333–339 DOI: 10.48083/CKYL2827 Systematic Review and Meta-Analysis of Response Rates in BCG-unresponsive Non–Muscle-Invasive Bladder Cancer: a Consensus Statement From the International Bladder Cancer Group Kyle M. Rose,1 Herney A. Garcia-Perdomo,2 Trinity J. Bivalacqua,3 J. Alfred Witjes,4 Joan Palou,5 Peter C. Black,6 Gary D. Steinberg,7 Seth P. Lerner,8 Sima P. Porten,9 Ashish M. Kamat,10 Roger Li1 1 Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, United States 2 Division of Urology/Urooncology, Department of Surgery, Universidad del Valle, Cali, Colombia 3 Department of Urology, University of Pennsylvania, Philadelphia, United States 4 Department of Urology, Radboud University Nijmegen Medical Centre, Mijmen, The Netherlands 5 Department of Urology, Fundacio Puigvert, Universitat Autonoma de Barcelona, Barcelona, Spain 6 Department of Urologic Sciences, University of British Columbia, Vancouver, Canada 7 Department of Urology, New York University Langone Health, New York, United States 8 Scott Department of Urology, Baylor College of Medicine, Houston, United States 9 Department of Urology, University of California San Francisco, San Francisco, United States 10 Department of Urology, MD Anderson Cancer Center, Houston, United States Abstract There is a critical need to establish reference response rates following bladder-sparing therapies administered in the setting of bacillus Calmete-Guerin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC). We sought to determine the efficacy of different interventions in recent trials accruing patients fulfilling the strict BCG- unresponsive definition established by the US Food and Drug Administration. We performed a systematic review and meta-analysis for clinical trials in the BCG-unresponsive disease space to include published and presented results. The primary endpoints were complete response rate for CIS±Ta/T1 tumors, recurrence-free rate for patients with papillary-only disease, and disease-free rate in studies enrolling both papillary CIS tumors (Ta/T1/CIS). I2 was used for assessing heterogeneity. Eleven studies using 9 different therapeutic agents in a total of 909 patients with BCG-unresponsive NMIBC were identified. The resulting outcomes at 3, 6, and 12 months were 44%, 38%, and 25% complete response rate in CIS±Ta/T1 tumors; 73%, 58%, and 48% recurrence-free rate in papillary-only; and 48%, 22%, and 43% disease-free rate in combined Ta/T1/CIS, respectively. Relatively low levels of heterogeneity were observed amongst studies restricted to papillary-only or CIS±Ta/T1 tumors. Future randomized controlled studies are needed and will likely require stratification between papillary-only and CIS±Ta/T1 tumors. Introduction The decision of the United States Food and Drug Administration (FDA) to accept single-arm phase II/III clinical trials of novel agents for the treatment of BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) in tumors with CIS emphasizes the importance of reference efficacy rates to help frame the decision for approval. A previous systematic review that aimed to provide such reference benchmarks uncovered significant heterogeneity in patients enrolled in previous NMIBC clinical trials regarding the number and timing of intravesical BCG instillation and the pathology of the subsequent recurrent tumor[1]. One method to circumvent these barriers is to homogenize the study population by using the standard BCG-unresponsive definition adopted by the FDA in clinical trial design[2]. Results from recent trials enrolling such patients will provide context for the interpretation of emerging data from ongoing clinical trials conducted in the BCG-unresponsive space. 333SIUJ.ORG SIUJ • Volume 3, Number 5 • September 2022 REVIEW mailto:Roger.Li%40moffitt.org?subject=SIUJ http://SIUJ.org Methods We performed a systematic review and meta-anal- ysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations. An updated search was performed using the previously published protocol (PROSPERO CRD42019130553)[1]. Full search proto- col, study review methodology, risk of bias assessment, and data synthesis are presented in Supplementary Appendix 1 (siuj.org). We included unpublished stud- ies from phase II-III clinical trials presented at national urologic/oncology conferences that strictly accrued patients with BCG-unresponsive disease. The primary endpoints were complete response rate (CRR) for CIS±Ta/T1 tumors, recurrence-free rate (RFR) for patients with papillary-only disease, and disease-free rate (DFR) in studies enrolling both papillary (Ta/T1) and CIS-containing patients as previously described (Ta/T1/CIS)[1,2]. We performed a meta-analysis of proportions with command metaprop and inverse method with logit transformed proportions and sensi- tivity analysis. Information was pooled with a random effect meta-analysis according to the heterogeneity expected. I2 was used for assessing heterogeneity. Results The initial search yielded 287 studies. After screening, 11 relevant studies were selected for analysis (Figure 1). Six studies were excluded in total. Four studies performed before the establishment of the BCG-unresponsive definition in 2015 were excluded as they enrolled patients with low-grade recurrences following BCG [3–6]. Another trial using CG0070 was excluded because of incomplete reporting[7]. One study was excluded because of the inclusion of BCG-intolerant patients rather than strictly those with BCG-unresponsive disease[8]. Studies with cohorts consisting of CIS- CIS±Ta/T1 tumors and papillary-only disease were ana lyzed separately, as prev iously described[9]. The included studies used 9 different therapeutic agents in a total of 909 patients with BCG-unresponsive NMIBC (Table 1). Of the reported study arms, 6 enrolled CIS±Ta/T1 tumors, 6 papillary-only tumors, and 4 Ta/T1/CIS tumors conjointly. The primary endpoints for CIS±Ta/T1, Ta/T1, and Ta/T1/CIS are listed by timepoints following ther- apy in Table 2 and illustrated in the forest plots in Figure 2. Only the durable 12-month CRR from QUILT 3.032 study[10] was used in the meta-anal- ysis as this was the only timepoint unequivocally reported. By limiting the analysis to studies enrolling patients fulfilling the BCG-unresponsive definition, we found more uniform but divergent response rates within the CIS±Ta/T1 and papillary-only cohorts, with 3-month, 6-month, and 12-month benchmarks that can help to inform emerging data from ongoing stud- ies. The only deviation was the 12-month CRR of 44% reported in the QUILT 3.032[10], increasing the over- all 12-month CRR from 21% to 25% and the I2 from 0% to 77% (Figure 2). In contrast, results from stud- ies conglomerating durable response rates between the 2 cohorts were marked by higher heterogeneity, support- ing the differential responsiveness to bladder-spar- ing treatment between CIS±Ta/T1 and papillary-only NMIBC. These results may ref lect different molecu- lar pathways leading to the development of CIS (orig- inating from chromosome 9p+q loss and TP53 and RB mutations) and papillary tumors (originating from FGFR alterations and 9q loss)[11]. Alternatively, diver- gent response and recurrence rates likely also reflect the fact that papillary tumors are amenable to complete trans- urethral resection but CIS usually is not[12]. The lack of uniformity amongst trial results further underscores differences in the mechanisms of action between the investigational agents and indicate differ- ences therapeutic efficacy. To further eliminate risks of bias and increase the rigor of the analysis, randomized controlled trials (RCT) are likely required in the future. As there is no universally accepted bladder-preserv- ing therapy for BCG-unresponsive NMIBC, there is a need to standardize treatment used in the control arm. Recent FDA approval suggests pembrolizumab is an option; however, many consider its efficacy insufficient to offset the observed toxicity profile and the significant cost[13]. Intravesical gemcitabine/docetaxel has also been proposed as an alternative by some on the basis of “expert opinion,” although its efficacy has not yet been established in prospective clinical trials. Moreover, shortages of BCG in many countries have hampered administration according to the SWOG protocol, limit- ing the number of patients fulfilling the BCG-unrespon- sive definition and creating a bottleneck for completing RCTs in this disease setting. This is the first meta-analysis to investigate the available studies that meet the strict definition of the BCG-unresponsive NMIBC definition adopted by the FDA in 2018[2]. Our results demonstrate a weighted average CRR of 38% at 6 months and 25% at 12 months in CIS±Ta/T1 BCG-unresponsive NMIBC. Of all completed trials, only one[10] achieved the 50% 6-month and 30% 12-month thresholds previously proposed to be clinically relevant[14,15] Notably, CRRs observed in trials using the 2 currently FDA-approved agents, pembrolizumab and valrubicin, fell short of these benchmarks regarding the 12-month duration of response. Several agents tested in similarly designed single-arm trials are currently under review by the FDA 334 SIUJ • Volume 3, Number 5 • September 2022 SIUJ.ORG REVIEW http://SIUJ.org http://SIUJ.org http://SIUJ.org http://SIUJ.org Records identified through databases searching (n= 287) Full-text articles and presentations assessed for eligibility (n=95) 11 studies Included in review Records after duplicates removed (n=185) In cl ud ed Sc re en in g El ig ib il it y Records screened (n=1404) Id en ti fi ca ti on 3 academic presentations 8 peer reviewed publications • Interim or incomplete results (26) • Non - clinical trial (8) • Not BCG unresponsive (27) • CG0070 (4) • Not relevant (10) • Reviews (4) • Prior to 2015 (5) Updates, letters, opinion papers excluded (n=90) Full-text articles excluded (n=84) FIGURE 1. Flow diagram of literature review for BCG-unresponsive non-muscle-invasive bladder cancer studies 335SIUJ.ORG SIUJ • Volume 3, Number 5 • September 2022 Systematic Review and Meta-Analysis of Response Rates in BCG-Unresponsive Non–Muscle-Invasive Bladder Cancer http://SIUJ.org TABLE 1. Presentations and publications in BCG-unresponsive NMIBC Authors Phase Date of Publication or Presentation Tumor Characteristics Agent Administered Navai et al. 2016[16] I 2016 Ta/T1/CIS Nadofaragene firadenovec Hahn et al. 2017[17] II 2017 Ta/T1/CIS Dovitinib Li et al. 2017[9] II 2017 Papillary-only MCNA a Li et al. 2017[9] II 2017 CIS±Ta/T1 MCNA a Shore et al. 2017[18] II 2017 Ta/T1/CIS Nadofaragene firadenovec O'Donnell et al. 2019[19] II 2019 Papillary-only CADI-05 b DeCastro et al. 2020[20] I 2020 Ta/T1/CIS Intravesical CGC c Shore 2021[21] III 2020 CIS±Ta/T1 Vicinium d Shore 2021[21] III 2020 Papillary-only Vicinium d Black et al. 2021[22] II 2021 CIS±Ta/T1 Atezolizumab Black et al. 2021[22] II 2021 Papillary-only Atezolizumab Balar et al. 2021[23] II 2021 CIS-containing Pembrolizumab Boorjian 2021[24] III 2021 CIS±Ta/T1 Nadofaragene firadenovec Boorjian 2021[24] III 2021 Papillary-only Nadofaragene firadenovec Chang et al. 2022[10] II/III 2022 CIS±Ta/T1 BCG + IL-15 Superagonist Chang et al. 2022[10] II/III 2022 Papillary-only BCG + IL-15 Superagonist a Mycobacterium phei cell wall-nucleic acid complex b Intradermal CADI-05 c Cabazitaxel, gemcitabine, cisplatin d rAd-IFNα/Syn3 336 SIUJ • Volume 3, Number 5 • September 2022 SIUJ.ORG REVIEW http://SIUJ.org and have reported CRR rates and 12-month durability that meet or exceed this bar. With the emerging data from recently completed and ongoing clinical trials, the CRR and durability threshold required for approval, particularly for patients with CIS, remains a moving target. If one or more new drugs receive FDA approval, this will provide clarity around these endpoints. Limitations of our study include a relatively low sample size of studies using a variety of different treat- ment agents. Additionally, variability in study protocols allowing for therapeutic re-induction following initial non-response and/or mandating post-therapy random bladder biopsy may affect response rates seen. Lastly, it is difficult to determine whether adjudication between CIS±Ta/T1 and papillary-only tumors was performed by central review in all included studies. Despite the hetero- geneity in the treatment agents used, we were successful in delineating a relatively narrow range of response rates at clinically relevant timepoints stratified by tumor stage to provide a frame-of-reference for emerging results from ongoing BCG-unresponsive clinical trials. Conclusion Our study indicates relatively uniform but disparate response rates to bladder-sparing therapies in BCG- unresponsive CIS±Ta/T1 and papillary-only NMIBC. To reduce risks of bias, randomized controlled studies with appropriate stratification of the 2 disease entities are likely to be required in the future. Consensus is also needed on the ideal therapeutic agent to be used in the control arm. Our results will help to formulate designs of future clinical trials and inform the interpretation of emerging data in this exciting treatment space. TABLE 2. Meta-analysis results by tumor characteristic and months following administration Time CIS±Ta/ T1 CRR (I2) Papillary-only Ta/ T1 RFR (I2) Ta/ T1/CIS DFR (I2) 3 months 44% (36%) n = 4 73% (0%) n = 3 48% (46%) n = 2 6 months 38% (58%) n = 3 58% (26%) n = 5 22% (63%) n = 3 12 months 25% (77%) n = 6 48% (49%) n = 6 43% (84%) n = 3 18 months 26% (88%) n = 2 50% (0%) n = 3 – 24 months 32% (95%) n = 2 40% (65%) n = 4 – CRR: complete response rate; RFR: recurrence-free rate; DFR: disease-free rate 337SIUJ.ORG SIUJ • Volume 3, Number 5 • September 2022 Systematic Review and Meta-Analysis of Response Rates in BCG-Unresponsive Non–Muscle-Invasive Bladder Cancer http://SIUJ.org References 1. Li R, Sundi D, Zhang J, Kim Y, Sylvester RJ, Spiess PE, et al. Systematic review of the therapeutic efficacy of bladder-preserving treatments for non-muscle-invasive bladder cancer following intravesical bacillus Calmette-Guerin. Eur Urol.2020;78(3):387-399. 2. United States Food and Drug Administration: BCG-unresponsive nonmuscle invasive bladder cancer: developing drugs and biologics for treatment guidance for industry. 2018:1-10. 3. Gacci M, Bartoletti R, Cai T, Nerozzi S, Pinzi N, Repetti F, et al. Intravesical gemcitabine in BCG-refractory T1G3 transitional cell carcinoma of the bladder: a pilot study. Urol Int.2006;76(2):106-111. 4. Gunelli R, Bercovich E, Nanni O, Ballardini M, Frassineti GL, Giovannini N, et al. Activit y of endovesical gemcitabine in BCG-refractor y bladder cancer patients: a translational study. Br J Cancer.2007;97(11):1499-1504. 5. Perdona S, Di Lorenzo G, Cantiello F, Damiano R, De Sio M, Masala D, et al. Is gemcitabine an option in BCG-refractory nonmuscle- invasive bladder cancer? A single-arm prospective trial. Anticancer Drugs.2010;21(1):101-106. 6. Skinner EC, Goldman B, Sakr WA, Petrylak DP, Lenz HJ, Lee CT, et al. SWOG S0353: Phase II trial of intravesical gemcitabine in patients with nonmuscle invasive bladder cancer and recurrence after 2 prior courses of intravesical bacillus Calmette-Guerin. J Urol.2013;190(4):1200-1204. 7. Packiam VT, Lamm DL, Barocas DA, Trainer A, Fand B, Davis RL 3rd, et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: Interim results. Urol Oncol.2018;36(10):440-447. 8. Hurle R GG, Colombo P, Santoro A, De Cobelli O, Trapani E, Nohales G, Llorente C, Duran-Merino R, Lazzeri M, editor Oncofid-P-B for the treatment of BCG unresponsive carcinoma in situ (CIS) of the bladder: preliminary results of European multicentre phase 1 study at the end of 12 consecutive weeks intensive course and during ongoing monthly maintenance phase. American Urologic Association; 2020: J Urol.2020 9. Li R, Amrhein J, Cohen Z, Champagne M, Kamat AM. Efficacy of mycobacterium phlei cell wall-nucleic acid complex (MCNA) in BCG-unresponsive patients. Bladder Cancer.2017;3(1):65-71. doi: 10.3233/BLC-160084 FIGURE 2. Forest plots of response rates from meta-analysis, stratified by tumor characteristic at 3 months (A), 6 months (B), and 12 months (C) Subgroup Total (95% CI) Heterogeneity: Tau2 = 0.2240; Chi2 = 30.05, df = 8 (P < 0.01); I2 = 73% Residual heterogeneity: Tau2 = NA; Chi2 = 7.39, df = 6 (P = 0.29); I2 = 19% CIS±Ta/T1 Papillary-only Ta/T1/CIS Total (95% CI) Total (95% CI) Total (95% CI) Heterogeneity: Tau2 = 0.0255; Chi2 = 4.67, df = 3 (P = 0.20); I2 = 36% Heterogeneity: Tau2 = 0; Chi2 = 0.86, df = 2 (P = 0.65); I2 = 0% Heterogeneity: Tau2 = 0.3413; Chi2 = 1.85, df = 1 (P = 0.17); I2 = 46% Balar et al 2021 Black et al 2021 Boorjian 2021 Chang et al 2022 Li et al 2017 Shore et al 2021 Black et al 2021 Boorjian 2021 Chang et al 2022 Li et al 2018 O’Donnell et al 2019 Shore et al 2021 DeCastro et al 2020 Hahn et al 2017 Navai et al 2016 Shore et al 2017 Study or Events 39.36 30.00 55.00 . . 36.00 . 35.00 . . 7.00 27.00 . . 2.00 23.00 Total 909 512 319 78 96 73 103 83 68 89 54 48 77 94 8 38 18 13 7 40 Weight 100.0% 57.9% 25.9% 16.2% 14.6% 13.9% 14.9% 0.0% 0.0% 14.5% 0.0% 11.9% 0.0% 0.0% 2.9% 11.1% 0.0% 0.0% 4.2% 12.0% IV, Random, 95% CI 0.53 [0.44; 0.63] 0.44 [0.38; 0.51] 0.73 [0.63; 0.81] 0.48 [0.24; 0.74] 0.41 [0.32; 0.51] 0.41 [0.30; 0.53] 0.53 [0.44; 0.63] 0.40 [0.31; 0.51] 0.73 [0.59; 0.84] 0.88 [0.46; 0.98] 0.71 [0.55; 0.83] 0.29 [0.07; 0.67] 0.58 [0.42; 0.72] 0 0.2 0.4 0.6 0.8 1 IV, Random, 95% CI A B Subgroup Total (95% CI) Heterogeneity: Tau2 = 0.2346; Chi2 = 35.47, df = 10 (P < 0.01); I2 = 72% Residual heterogeneity: Tau2 = NA; Chi2 = 15.59, df = 8 (P = 0.05); I2 = 49% CIS±Ta/T1 Papillary-only Ta/T1/CIS Total (95% CI) Total (95% CI) Total (95% CI) Heterogeneity: Tau2 = 0.0777; Chi2 = 4.83, df = 2 (P = 0.09); I2 = 59% Heterogeneity: Tau2 = 0.0334; Chi2 = 5.4, df = 4 (P = 0.25); I2 = 26% Heterogeneity: Tau2 = 1.0675; Chi2 = 5.36, df = 2 (P = 0.07); I2 = 63% Balar et al 2021 Black et al 2021 Boorjian 2021 Chang et al 2022 Li et al 2017 Shore et al 2021 Black et al 2021 Boorjian 2021 Chang et al 2022 Li et al 2018 O’Donnell et al 2019 Shore et al 2021 DeCastro et al 2020 Hahn et al 2017 Navai et al 2016 Shore et al 2017 Study or Events . 20 42 . 30 . 35 30 . 46 6 22 . 1 1 17 Total 909 512 319 78 96 73 103 83 68 89 54 48 77 94 8 38 18 13 7 40 Weight 100.0% 36.0% 48.5% 15.5% 0.0% 11.5% 12.7% 0.0% 11.9% 0.0% 11.0% 10.8% 0.0% 12.6% 3.9% 10.2% 0.0% 2.6% 2.5% 10.4% IV, Random, 95% CI 0.47 [0.38; 0.56] 0.38 [0.28; 0.48] 0.58 [0.50; 0.66] 0.22 [0.06; 0.55] 0.27 [0.18; 0.39] 0.41 [0.31; 0.51] 0.44 [0.32; 0.57] 0.65 [0.51; 0.77] 0.62 [0.47; 0.76] 0.49 [0.38; 0.59] 0.75 [0.35; 0.97] 0.58 [0.41; 0.74] 0.08 [0.00; 0.36] 0.14 [0.00; 0.58] 0.42 [0.27; 0.59] 0 0.2 0.4 0.6 0.8 1 IV, Random, 95% CI 338 SIUJ • Volume 3, Number 5 • September 2022 SIUJ.ORG REVIEW http://SIUJ.org 10. Chang SS, Chamie K, Gonzalgo ML, Kramolowsky EV, Sexton WJ, Reddy SK, et al. 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. J Clin Oncol.2022;40(6 suppl):431. doi: 10.1200/ JCO.2022.40.6_suppl.431 11. Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer.2015;15(1):25-41. 12. Dalbagni G. The management of superficial bladder cancer. Nat Clin Pract Urol.2007;4(5):254-260. doi: 10.1038/ncpuro0784 13. Wymer KM, Sharma V, Saigal CS, Chamie K, Litwin MS, Packiam VT, et al. Cost-effectiveness analysis of pembrolizumab for bacillus Calmette-Guerin-unresponsive carcinoma in situ of the bladder. J Urol.2021;205(5):1326-1335. 14. Jarow JP, Lerner SP, Kluetz PG, Liu K, Sridhara R, Bajorin D, et al. Clinical trial design for the development of new therapies for nonmuscle-invasive bladder cancer: report of a Food and Drug Administration and American Urological Association public workshop. Urology.2014;83(2):262-264. 15. Kamat AM, Sylvester RJ, Bohle A, Palou J, Lamm DL, Brausi M, et al. Definitions, end points, and clinical trial designs for non-muscle- invasive bladder cancer: recommendations from the International Bladder Cancer Group. J Clin Oncol.2016;34(16):1935-1944. 16. Navai N, Benedict WF, Zhang G, Abraham A, Ainslie N, Shah JB, et al. Phase 1b trial to evaluate tissue response to a second dose of intravesical recombinant adenoviral interferon alpha2b formulated in syn3 for failures of bacillus Calmette-Guerin (BCG) therapy in nonmuscle invasive bladder cancer. Ann Surg Oncol.2016;23(12):4110-4114. 17. Hahn NM, Bivalacqua TJ, Ross AE, Netto GJ, Baras A, Park JC, et al. A phase II trial of dovitinib in BCG-unresponsive urothelial carcinoma with FGFR3 mutations or overexpression: Hoosier Cancer Research Network Trial HCRN 12-157. Clin Cancer Res.2017;23(12):3003-3011. 18. Shore ND, Boorjian SA, Canter DJ, Ogan K, Karsh LI, Downs TM, et al. Intravesical rAd-IFNalpha/Syn3 for patients with high-grade, bacillus Calmet te-Guerin-refractor y or relapsed non-muscle- invasive bladder cancer: a phase II randomized study. J Clin Oncol.2017;35(30):3410-3416. 19. O’Donnell MA, Singh S, Sood R, Amlani J, Krishnamoorthy H, Shukla K, et al. A clinical trial of the intradermal TLR2 agonist CADI-05 for BCG recurrent and unresponsive non-muscle invasive bladder cancer. Bladder Cancer.2019;5:171-180. doi: 10.3233/BLC-190211 20. DeCastro GJ, Sui W, Pak JS, Lee SM, Holder D, Kates MM, et al. A phase I trial of intravesical cabazitaxel, gemcitabine and cisplatin for the treatment of nonmuscle invasive bacillus Calmette-Guerin unresponsive or recurrent/relapsing urothelial carcinoma of the bladder. J Urol.2020;204(2):247-253. 21. Shore ND, ed. Phase 3 results of vicinium in BCG-unresponsive non-muscle invasive bladder cancer. American Urologic Association Annual Meeting; June 2020; Virtual. 22. Black PC, Tangen CM, Singh P, McConkey DJ, Lucia S, Lowrance WT, et al. Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT # 02844816). J Clin Oncol.2021;39(15 suppl):4541-. 23. Balar AV, Kamat AM, Kulkarni GS, Uchio EM, Boormans JL, Roumiguie M, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol.2021;22(7):919-930. doi: 10.1016/S1470-2045(21)00147- 9. Epub 2021 May 26. 24. Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol.2021;22(1):107-117. doi:https://doi.org/10.1016/S1470-2045(20)30540-4 C Subgroup Total (95% CI) Heterogeneity: Tau2 = 0.4214; Chi2 = 83.57, df = 14 (P < 0.01); I2 = 83% Residual heterogeneity: Tau2 = NA; Chi2 = 44.84, df = 12 (P < 0.01); I2 = 73% CIS±Ta/T1 Papillary-only Ta/T1/CIS Total (95% CI) Total (95% CI) Total (95% CI) Heterogeneity: Tau2 = 0.2276; Chi2 = 22.17, df = 5 (P < 0.01); I2 = 77% Heterogeneity: Tau2 = 0.0813; Chi2 = 9.96, df = 5 (P = 0.08); I2 = 50% Heterogeneity: Tau2 = 2.2936; Chi2 = 12.71, df = 2 (P < 0.01); I2 = 84% Balar et al 2021 Black et al 2021 Boorjian 2021 Chang et al 2022 Li et al 2017 Shore et al 2021 Black et al 2021 Boorjian 2021 Chang et al 2022 Li et al 2018 O’Donnell et al 2019 Shore et al 2021 DeCastro et al 2020 Hahn et al 2017 Navai et al 2016 Shore et al 2017 Study or Events 18 11 25 37 18 19 28 21 44 33 5 19 15 . 0 14 Total 909 512 319 78 96 73 103 83 68 89 54 48 77 94 8 38 18 13 7 40 Weight 100.0% 45.5% 41.6% 13.0% 7.6% 7.0% 7.8% 7.9% 7.5% 7.6% 7.5% 7.3% 7.8% 7.9% 3.9% 7.1% 4.5% 0.0% 1.5% 7.0% IV, Random, 95% CI 0.37 [0.28; 0.46] 0.25 [0.17; 0.33] 0.48 [0.40; 0.56] 0.43 [0.10; 0.84] 0.19 [0.12; 0.28] 0.15 [0.08; 0.25] 0.24 [0.16; 0.34] 0.45 [0.34; 0.56] 0.26 [0.17; 0.39] 0.21 [0.13; 0.31] 0.52 [0.38; 0.66] 0.44 [0.29; 0.59] 0.57 [0.45; 0.68] 0.35 [0.26; 0.46] 0.62 [0.24; 0.91] 0.50 [0.33; 0.67] 0.83 [0.59; 0.96] 0.00 [0.00; 0.41] 0.35 [0.21; 0.52] 0 0.2 0.4 0.6 0.8 1 IV, Random, 95% CI 339SIUJ.ORG SIUJ • Volume 3, Number 5 • September 2022 Systematic Review and Meta-Analysis of Response Rates in BCG-Unresponsive Non–Muscle-Invasive Bladder Cancer http://SIUJ.org