










































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.

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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 

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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

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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

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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

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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

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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

