










































Bladder Cancer

Proceedings from the  
SIU B2B Uro-Oncology:  
GU Cancers Triad  
Virtual Meeting 
May 21–22, 2021

www.siu-urology.org

#B2BGUCancerTriad

https://www.siu-urology.org
https://twitter.com/search?q=%23B2BGUCancerTriad


PROCEEDINGS FROM THE SIU B2B URO-ONCOLOGY: GU CANCERS TRIAD • MAY 21–22, 2021 – SIUJ VOLUME 2, SUPPLEMENT 1, JULY 2021

7

B2B: Bladder Cancer Summary

Peter C. Black,a,* Ashish M. Kamat,b,† Angela B. Smith,c Sima Porten,d Renu Eapen,e,f Carmen Mir,g  
Jeremy Teoh,h Tilman Todenhöfer,i Tian Zhang,j Kilian M. Gust,k Srikala Sridhar,l  Simon Tanguaym,‡

aDepartment of Urologic Sciences, University of British Columbia, Vancouver, Canada bDepartment of Urology, The University of  
Texas MD Anderson Cancer Center, Houston, United States cDepartment of Urology, University of North Carolina at Chapel Hill, 
Chapel Hill, United States dDepartment of Urology, University of California, San Francisco, United States ePeter MacCallum Cancer 
Centre, Melbourne, Australia fOlivia Newton John Cancer Centre & Austin Health, Melbourne, Australia gCase Western Reserve 
University, Cleveland, United States hDepartment of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong 
Kong, China iEberhard-Karls University Tübingen, Tübingen, Germany jDepartment of Medicine, Duke Cancer Institute, Durham, 
United States kDepartment of Urology, Medical University of Vienna, Vienna, Austria lPrincess Margaret Cancer Centre, University of 
Toronto, Toronto, Canada mDivision of Urology, McGill University, Montreal, Canada *Chair of the Scientific Programme Committee 
†Co-Chair of the Scientific Programme Committee (BCa) ‡Co-Chair of the Scientific Programme Committee (RCC)

The Bench-to-Bedside Uro-Oncology GU Cancer Triad Meeting was organized by the Société 
Internationale d’Urologie and was held online on May 21st and 22nd, 2021. The session on 
bladder cancer (BCa) took place on the morning of Friday, May 21st, and was chaired by  
Dr. Peter C. Black (Canada) and Dr. Ashish Kamat (United States). This session covered practice-
changing advances on the horizon for BCa, the use of urine markers in BCa management, 
evolving therapies for non-muscle-invasive BCa (NMIBC), and recent advances for systemic 
therapy for muscle-invasive BCa (MIBC) and advanced urothelial carcinoma (UC). The faculty 
also discussed how to manage immune-related adverse events (AEs).

Dr. Angela Smith (United States) presented five  
practice-changing advances on the horizon across the 
disease spectrum of BCa and upper tract UC (UTUC). 
One of these advances is in the treatment of low-grade 
intermediate-risk NMIBC[1,2]. These are tumours that 
have high rates of recurrence but low risk of progres-
sion[2]. In this disease setting, transurethral resection 
of bladder tumour (TURBT) plus intravesical therapy is 
considered standard of care[1,3], with mitomycin and 
gemcitabine instillation after TURBT being shown to 
reduce the risk of recurrence[4,5]. However, repeat 
TURBTs expose patients to risks of repetitive anesthe-
sia and surgically related complications[6].

The use of UGN-102, a thermoreversible hydro-
gel containing mitomycin, is being investigated for 
nonsurgical chemoablation in patients with low-grade 
intermediate-risk NMIBC in the phase 2b OPTIMA II 
trial[7]. In an interim analysis, complete response (CR) 
at 3 months was observed in 65% of patients (95% 
CI 52%–77%) following treatment with UGN-102. In 
the safety analysis, 91% of patients experienced ≥1 
AE, with the most common AEs occurring in ≥5% 
of patients related to lower urinary tract symptoms 
(LUTS), such as dysuria (91%), pollakiuria (41%), and 

hematuria (19%)[7]. With an estimated durability of 
response at the 12-month follow-up of 60%, these 
interim data demonstrate that primary chemoablation 
of low-grade intermediate-risk NMIBC using UGN-102 
results in a significant treatment response and encour-
aging durability, and may provide an alternative to 
TURBT treatment for patients in this disease setting[7]. 
Chemoablation with UGN-102 vs. TURBT is now being 
investigated in the phase 3 trial ATLAS[8].

There have been multiple advances in the treat-
ment of high-grade bacillus Calmette-Guérin (BCG)-
refractory NMIBC, including the U.S. Food and Drug 
Administration (FDA) approval of pembrolizumab in 
this setting for carcinoma in situ (CIS) and the recently 
published results of the novel gene therapy nado-
faragene firadenovec in this population[9,10]. Among 
the developments on the horizon is the investigation 
of combination intravesical gemcitabine and pembroli-
zumab therapy to treat BCG-unresponsive NMIBC in 
the phase 2 Alliance A031803 trial[11]. This trial is also 
assessing correlations of tumour genomic aberrations 
with therapy response, the results of which may assist 
in future patient selection for treatment.

DOI: 10.48083/NJCD1236



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PROCEEDINGS FROM THE SIU B2B URO-ONCOLOGY: GU CANCERS TRIAD • MAY 21–22, 2021 – SIUJ VOLUME 2, SUPPLEMENT 1, JULY 2021

B2B: Bladder Cancer Summary

In the localized MIBC space, RETAIN BLADDER is a 
phase 2 trial investigating a risk-adapted approach to 
treatment that may result in bladder preservation[12]. 
Treatment was determined according to tumour stage 
and mutation status following neoadjuvant chemo-
therapy (NAC) and TURBT. Patients with no residual 
tumour (cT0) and positive mutations proceeded to 
active surveillance. In an interim analysis of clinically 
meaningful endpoints, 39% of patients proceeded to 
active surveillance. At the data cut-off, 77% of patients 
on active surveillance were alive, had not developed 
metastasis, and had not undergone radical cystec-
tomy. Based on these favourable results, the phase 2 
RETAIN trial was initiated to investigate a risk-enabled 
treatment approach following neoadjuvant immuno-
chemotherapy in MIBC[13].

Dual immunotherapy is showing encouraging 
results in the first-line treatment of locally advanced 
or metastatic BCa. In an updated analysis of cispla-
tin-ineligible patients in the EV-103 trial, enfortumab 
vedotin plus pembrolizumab resulted in a 73.3% con-
firmed objective response rate (ORR), regardless of 
programmed death-ligand 1 (PD-L1) expression, and 
promising 93% tumour reduction[14]. Response to 
treatment appears to occur relatively quickly, with 88% 
of patients demonstrating response at first assessment 
(week 9±1 week). The median progression-free sur-
vival (PFS) in this patient cohort was 12.3 months and 
both median overall survival (OS) as well as duration 
of response (DOR) have not been reached. In addition 
to the positive efficacy results, treatment with enfor-
tumab vedotin plus pembrolizumab has a favourable 
toxicity profile, with only 16% of patients experiencing 
serious treatment-related AEs (TRAEs).

In the UTUC setting, the phase 3 trial PROOF 302 
is evaluating the efficacy and safety of infigratinib as 
adjuvant therapy in patients with high-risk invasive 
UC and susceptible FGFR3 alterations[15]. As a large 
proportion of patients with UTUC shows alterations 
in FGFR3[16], infigratinib, a fibroblast growth factor 
receptor (FGFR) inhibitor, may be an attractive thera-
peutic agent for this population.

During the Q&A period, Dr. Smith was asked how 
the toxicities of novel bladder-sparing treatments 
will compare to those of current therapeutic options. 

According to Dr. Smith, patient-reported outcomes 
will play an important role in the toxicity evaluation of 
new therapies, which will also impact the treatment 
selection. As she pointed out, different treatments 
may differ considerably in terms of patient experience, 
regardless of similar efficacy. Another important aspect 
that will affect treatment selection is the frequency of 
treatment delivery. Therapies that require fewer visits 
to the hospital may pose a reduced logistical and finan-
cial burden that would ultimately benefit the patient.

The following session was a panel discussion hosted 
by the SIU Innovators and provided insights on the 
selection and use of urinary biomarkers in the various 
stages of BCa diagnosis, management, and follow-up. 
Dr. Sima Porten (United States) moderated the discus-
sion with input from a panel of experts comprising Dr. 
Renu Eapen (Australia), Dr. Carmen Mir (Spain), and  
Dr. Jeremy Teoh (Hong Kong). 

The case was a 50-year-old male who received ini-
tial treatment with TURBT with gemcitabine for a low-
grade Ta tumour. At the 3-month follow-up, cytology 
showed atypical urothelial cells (Paris 3 classification), 
despite no evidence of disease by cystoscopy. The 
panelists discussed if cytology is commonly per-
formed at the time of cystoscopy, the use of the Paris 
classification by cytopathologists, and whether other 
urinary biomarkers are routinely used for BCa diag-
nosis. The use of cytology at the time of surveillance 
cystoscopy is variable and not always performed for 
low-grade tumours, and the Paris classification is not 
always adopted. While cytology is considered the gold 
standard in this setting, the panelists highlighted other 
commercially available urinary biomarker tests that 
may be used in adjunction. ADXBLADDER™ is an 
enzyme-linked immunosorbent assay (ELISA) test that 
detects MCM5 in urine, a known biomarker for bladder 
tumours[17]. Other options include gene expression 
analysis with messenger RNA (mRNA)-based tests 
for BCa biomarkers, such as Xpert® Bladder Cancer 
Monitor[18] and Cxbladder Monitor™ tests[19]. 
Another biomarker test is UroVysion™, a multi-colour 
fluorescence in situ hybridization (FISH) assay to detect 
chromosome aberrations associated with urothelial 
tumour cells[20].



B2B: BLADDER CANCER SUMMARY

9

B2B: Bladder Cancer Summary

The discussion continued on to which steps would 
be taken following a positive cytology for Paris 4 or 
Paris 5, which indicate a higher risk for high-grade 
UC[21]. If no evidence of disease is seen by cystoscopy, 
enhanced imaging techniques, such as photodynamic 
diagnosis or narrow band imaging (NBI)[22], should be 
implemented to evaluate the presence of UC. Random 
biopsies of the bladder as well as selective upper tract 
urine cytology may also be considered, particularly 
in patients with unexplained positive urine cytology. 
Upper tract urine cytology may be performed by urine 
aspiration or lavage cytology and has a high sensitivity 
of up to 69.9% for high-grade UTUC[23].

Next, the case proceeded with the patient being 
diagnosed with high-risk NMIBC and starting BCG 
induction. While not routinely used in clinical prac-
tice, urinary biomarkers may play an important role in 
predicting response to BCG therapy and evaluating 
patient prognosis. UroVysion FISH analysis has been 
shown to predict disease recurrence and progression 
in patients receiving BCG[24]. This may be particularly 
useful for guiding treatment discussions with patients. 

Following BCG maintenance, no evidence of 
disease was found by cystoscopy and cytology was 
negative during surveillance for the patient case. 
However, the number of procedures, frequency of 
hospital visits, and current risk of COVID-19 may pose 
an important burden on the patient. In this setting, 
some urinary biomarker tests demonstrate potential 
for providing a noninvasive alternative to cystoscopy. 
Bladder EpiCheck is a kit that detects disease-spe-
cific DNA methylation patterns in BCa patients with 
high negative predictive values (NPV)[25]. However, 
this test is not routinely implemented in the clinical 
practice. Other options for patient surveillance may 
include ADXBLADDER[26] and Xpert Bladder Cancer 
Monitor[27], both of which have shown high NPV. Dr. 
Porten highlighted the use of Cxbladder Monitor dur-
ing the COVID-19 pandemic as an option for patient 
surveillance at home that has been adopted at the 
UCSF Medical Center.

In the patient case, surveillance with Cxbladder 
Monitor showed values above cut-off. Cystoscopy was 
performed, leading to a diagnosis of MIBC. The patient 
received NAC followed by radical cystoprostatectomy 

with lymph node dissection and neobladder diver-
sion with favourable pathology. Given the limited 
evidence for urinary biomarkers in this setting, com-
puted tomography (CT) scans and urine cytology are 
typically the routine options for patient surveillance. 
However, emerging data may provide new insights on 
the use of urinary biomarkers for post-urinary diversion 
surveillance. 

Next, Dr. Tilman Todenhöfer (Germany) discussed 
the evolving treatments for NMIBC by focusing on 
three main topics: 1) identifying predictive molecular 
markers of BCG treatment response, 2) emerging treat-
ment options for BCG-unresponsive patients, and 3) 
novel therapy delivery approaches in NMIBC.

Recent studies examining the molecular alterations 
of NMIBC have led to significant improvements in 
understanding the disease. In a recent report of the 
UROMOL project, four molecular subtypes of NMIBC 
with differing recurrence rates were identified based 
on the transcriptomic analysis of 834 patients[28].  
In the same study, chromosomal instability was 
also analyzed, leading to the identification of three 
genomic classes associated with varying risk of disease 
progression. Both the molecular subtype and genomic 
class may have important implications for predicting 
treatment response.

BCG is currently the gold standard for treatment 
of BCG-naïve NMIBC and results in high rates of high-
grade recurrence-free survival (RFS), as demonstrated 
in a recent retrospective analysis of a contemporary 
patient cohort[29]. Despite these excellent outcomes, 
there is an ongoing need for alternative treatment 
approaches to BCG in NMIBC. First, BCG shortage 
is an ongoing issue and limits the access of a high 
proportion of patients to this therapy, leading to sig-
nificant impact on patient outcomes[30]. Second, BCG 
intolerance is an ongoing issue, regardless of recent 
decreases in treatment discontinuation due to TRAEs. 
Lastly, many patients with NMIBC do not respond to 
BCG therapy and require other treatment approaches. 
Therefore, predicting BCG response is important to 
guide treatment decisions in NMIBC. Recent studies 
have further advanced this field by identifying genomic 
and histological markers for patient stratification and 
treatment outcome prediction[31–33].



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PROCEEDINGS FROM THE SIU B2B URO-ONCOLOGY: GU CANCERS TRIAD • MAY 21–22, 2021 – SIUJ VOLUME 2, SUPPLEMENT 1, JULY 2021

B2B: Bladder Cancer Summary

Treatment of BCG-unresponsive disease continues 
to be a major challenge in NMIBC. Novel treatment 
options under investigation in this setting include 
intravesical approaches with nadofaragene firad-
enovec[34], oportuzumab monatox[35], and N803/
BCG[36], as well as systemic options with immune 
checkpoint inhibitors (ICIs), such as atezolizumab[37] 
and pembrolizumab[38]. While all of these agents are 
showing encouraging outcomes, treatment tolerability 
in this setting appears slightly improved with intravesi-
cal approaches. However, the role of ICI may increase 
in the NMIBC setting as the results of multiple ongo-
ing trials in BCG-naïve high-risk disease (Potomac, 
Alban, and CREST), BCG induction failure (KN676 
and CheckMate 7G8), and BCG-unresponsive NMIBC 
(CheckMate 9UT and A031803) become available. In 
addition, a novel approach for ICI therapy was recently 
presented. In SUBDUE-1, a dose-finding phase 1b trial, 
intravesical injection of durvalumab is under investiga-
tion for patients with NMIBC[39], an approach that has 
shown promising results in the pre-clinical studies[40].

Several ongoing trials are also investigating the use 
of targeted systemic therapies, currently approved for 
metastatic BCa, in patients with BCG-unresponsive 
disease. A recent study in patients with FGFR-positive 
NMIBC demonstrated promising efficacy results fol-
lowing treatment with infigratinib. However, TRAE in 
all patients led to discontinuation of treatment[41]. In 
order to improve tolerability of FGFR-targeted therapy 
in NMIBC, ongoing trials are evaluating FGFR inhibitor 
doses lower than those used in the metastatic set-
ting. In a current phase 2 trial led by Dr. Noah Hahn at 
Johns Hopkins, a 9-mg dose of pemigatinib is being 
investigated to treat patients with NMIBC, which 
corresponds to only two-thirds of the dose used in 
metastatic BCa[42].

Other studies are focusing on improving the 
efficacy and delivery of intravesical chemotherapy. 
Hyperthermia-induced mitomycin, an approach fre-
quently used in centres in Europe, has become the 
focus of recent investigations. In a retrospective study 
of patients with BCG-unresponsive NMIBC, conductive 
chemohyperthermia with mitomycin led to 12-month 
RFS rates >50% in patients with CIS[43]. Another way 
of improving the efficacy of intravesical treatment is 

the use of a slow-delivery device (TAR-200, GemRIS™) 
that is inserted in the bladder, which allows continuous 
delivery and exposure to chemotherapy[44]. Two clin-
ical trials will evaluate the use of TAR-200 in patients 
with NMIBC. In an ongoing, prospective, randomized 
phase 2b trial, treatment delivery with TAR-200 is being 
compared with standard of care intravesical chemo-
therapy in patients with BCG-unresponsive disease 
as monotherapy or in combination with the ICI cetreli-
mab[45]. Another randomized, phase 3 clinical trial will 
investigate the efficacy of TAR-200 chemotherapy in 
combination with cetrelimab compared to BCG ther-
apy in BCG-naïve NMIBC, with disease-free survival 
(DFS) as the primary endpoint.

In the Q&A period, Dr. Todenhöfer provided his 
highlights of treatment advances in NMIBC to look 
forward to in the next year. One of the highlights is 
the development of new drug classes that exceed the 
efficacy of chemotherapy, such as nadofaragene firad-
enovec and oportuzumab monatox. According to Dr. 
Todenhöfer, these therapies may have an important 
role not only in the treatment of BCG-unresponsive 
patients, but also in earlier settings. Another highlight 
is the advance of systemic therapy for NMIBC. As 
pointed out by Dr. Todenhöfer, these advances will be 
influenced by important treatment-related toxicities, 
which may be less tolerable in patients with NMIBC. 

The following talk was by Dr. Tian Zhang (United 
States) who discussed the advances in systemic ther-
apy for MIBC and advanced UC in 2021. The current 
treatment landscape for metastatic UC comprises plat-
inum-based chemotherapy as first-line regimen and 
switch maintenance with the PD-L1 inhibitor avelumab, 
recently highlighted in the JAVELIN Bladder 100 
study[46]. Treatment then may follow with enfortumab 
vedotin for all patients or erdafitinib for those pre-
senting with FGFR2 and FGFR3 genomic alterations. 
Multiple clinical trials are ongoing and sacituzumab 
govitecan recently received FDA accelerated approval 
in the third-line setting[47]. 

The successful results of different immunothera-
peutic agents for metastatic disease have fomented 
several trials aiming to bring those treatment advances 
into earlier disease settings. In MIBC, chemotherapy 
in combination with pembrolizumab was investigated 



B2B: BLADDER CANCER SUMMARY

11

B2B: Bladder Cancer Summary

as neoadjuvant therapy prior to radical cystectomy 
in the LCCC 1520 trial[48]. The primary endpoint has 
been met, with 56% of patients achieving a down-
staging pathologic response rate <pT2N0M0 and 
36% having a pathologic CR to treatment, along with 
a generally safe toxicity profile. A number of clinical 
trials have been reported in recent years using neo-
adjuvant immunotherapy or combination chemoim-
munotherapy in MIBC[48–53]. Most of these studies 
have enrolled patients with T2, T3, T4, or N1 disease 
and demonstrated the effect of immunotherapies on 
pathologic response at the time of cystectomy. Several 
trials are ongoing and aim to examine the role of ICIs, 
antibody-drug conjugates (ADCs), and combination 
therapy in the neoadjuvant treatment of MIBC.

In the adjuvant setting, the CheckMate 274 trial 
investigated the role of nivolumab in the treatment 
of MIBC following cystectomy, in both patients with 
prior neoadjuvant cisplatin-based chemotherapy 
and those without NAC and ineligible for adjuvant 
treatment[54]. Treatment with nivolumab compared 
to placebo resulted in a significantly longer median 
DFS, the primary endpoint, in the intent-to-treat (ITT) 
population (21.0 vs. 10.9 months, HR=0.70 [98.31% CI 
0.54–0.89]; P<0.001), as well as in a subset of patients 
with PD-L1 expression ≥1% (not reached vs. 10.8 
months, HR=0.53 [98.87% CI 0.34–0.84]; P<0.001). 
Common AEs included pruritus, fatigue, diarrhea, rash, 
and increased lipase, which are expected reactions 
from treatment with immunotherapies. Additional tri-
als currently enrolling patients to examine the role of 
adjuvant immunotherapies in MIBC and UTUC include 
the AMBASSADOR trial (pembrolizumab vs. observa-
tion[55]) and, with targeted therapies for FGFR-altered 
urothelial cancer, the PROOF-302 trial (infigratinib vs. 
placebo[15]).

Results of the JAVELIN Bladder 100 trial have 
changed practice in the locally advanced and met-
astatic UC setting. In patients with unresectable dis-
ease, treatment with avelumab and best supportive 
care (BSC) resulted in significant improvements in 
OS (HR=0.69 [95% CI 0.56–0.86]; P<0.001) and PFS 
(HR=0.62 [95% CI 0.52–0.75]; P<0.001) compared to 
BSC alone[46]. The benefit of adding avelumab to 
BSC was observed in patients who had achieved CR, 

partial response (PR), or stable disease (SD) after initial 
chemotherapy. While shorter median OS and PFS were 
observed in patients with PR or SD, additional treat-
ment options may be available for this very frail patient 
population in the post-avelumab setting. 

Additionally, in the metastatic UC setting, the posi-
tive results of the phase 3 trial EV-301 have cemented 
enfortumab vedotin for treatment of patients with 
refractory disease and prior immunotherapy[56]. In the 
trial, treatment with enfortumab vedotin resulted in sig-
nificantly improved OS (12.88 vs. 8.97 months, HR=0.70 
[95% CI 0.56–0.89]; P=0.0142) and PFS (5.554 vs. 3.72 
months, HR=0.62 [95% CI 0.51–0.75]; P<0.00001) 
compared to chemotherapy. Among the grade 3 or 
higher AEs observed in this trial, maculopapular rash 
occurred more frequently in patients who received 
enfortumab vedotin (7% vs. 0%), whereas decreased 
neutrophil count (6% vs. 13%), decreased white blood 
cell (1% vs. 7%), and febrile neutropenia (1% vs. 5%) 
were more frequently observed in the chemotherapy 
group. Other ongoing trials (EV-302 and EV-103) are 
evaluating the use of enfortumab vedotin alone or in 
combination with pembrolizumab or chemotherapy as 
a first-line treatment option for metastatic UC[51,57].

During the Q&A, Dr. Zhang provided her insights 
on first- and second-line therapy recommendations for 
metastatic UC. Platinum-based chemotherapy is still 
the primary option for eligible patients. Once achiev-
ing SD, Dr. Zhang recommends that patients undergo 
maintenance treatment with avelumab. Second-line 
options will often include enfortumab vedotin for all 
patients or erdafitinib for patients with FGFR alter-
ations. With each line of therapy in metastatic UC, 
the goal is to extend patient survival while preserving 
quality of life. She also pointed out that other options 
may become available in earlier disease settings, as 
many ongoing clinical trials are evaluating systemic 
therapy options in the localized and adjuvant settings. 
In addition, Dr. Zhang addressed the ideal timing to 
sequence tumour tissue in order to guide treatment 
decisions in the metastatic setting. She recommends 
that sequencing be performed following cystectomy, 
given the amount of tumour tissue available, particu-
larly for patients who have residual disease after neo-
adjuvant treatment. 



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PROCEEDINGS FROM THE SIU B2B URO-ONCOLOGY: GU CANCERS TRIAD • MAY 21–22, 2021 – SIUJ VOLUME 2, SUPPLEMENT 1, JULY 2021

B2B: Bladder Cancer Summary

The session concluded with a case-based discus-
sion on management of immune-related AEs and 
toxicities, not specifically related to BCa. This was led 
by Dr. Kilian Gust (Austria), with the discussion based 
on the input of Dr. Srikala Sridhar (Canada), Dr. Tilman 
Todenhöfer (Germany), and Dr. Tian Zhang (United 
States).

The first case was a 54-year-old female initially diag-
nosed with and treated for high-risk NMIBC who pro-
gressed to MIBC. Following a radical cystectomy, the 
patient presented with lymph node metastasis in the 
surgical field. At this time, the patient started treatment 
with atezolizumab after enrolling in the SAUL trial[58]. 
After the first treatment cycle, the patient presented 
with a marked increase in thyroid-stimulating hormone 
(TSH), characteristic of thyroiditis. This AE is commonly 
observed in patients receiving immunotherapies. If 
the patient is asymptomatic or presents mild symp-
toms, immune-related thyroid dysfunction does not 
require immediate management or discontinuation of 
immunotherapy. Changes in TSH, T3, and T4 hormone 
levels should be closely monitored. Early referral to an 
endocrinologist may be considered[59]. The patient 
continued treatment with atezolizumab and reached 
CR. Over time, she developed hypothyroidism, which 
was managed with thyroid hormones. At cycle 49 of 
atezolizumab, the patient relapsed and was treated 
with chemotherapy, after which she achieved PR and 
was put on avelumab maintenance. After receiving the 
first dose, the patient presented with fever and chills. 
These infusion reactions are commonly seen with ave-
lumab[46] and may be prevented with premedication. 

The second case was a 76-year-old male with poor 
prognosis for MIBC. After the patient refused NAC, 
he underwent radical cystectomy and recovered well 
after surgery. Results of CheckMate 274 trial suggest 
that this patient could benefit from adjuvant treatment 
with nivolumab[54], which is not yet approved in this 
setting. Two weeks after receiving the first dose of 
nivolumab, the patient reported feeling unwell. His 
blood work showed altered liver function. At this point, 
it is important to put the immunotherapy treatment on 
hold, discuss with the patient the possibility of a TRAE, 
and consider referral to a hepatologist. Management 

of altered liver function may include prednisolone. If 
tests do not show improvement, a liver biopsy may be 
performed to guide alternative management deci-
sions[59]. The patient in this case responded well to 
intravenous methylprednisolone and resumed immu-
notherapy with close monitoring of liver function. In an 
alternative scenario in which the patient had received 
NAC, it would be important to discuss potential TRAEs 
prior to starting treatment with nivolumab. Patients in 
this setting who have no signs of active disease may 
be less tolerant to AEs resulting from immunotherapy.

The last case was a 67-year-old male with interme-
diate-risk renal cell carcinoma (RCC) who underwent 
cytoreductive nephrectomy prior to enrolling in the 
phase 3 CLEAR trial, in which the patient received 
pembrolizumab plus lenvatinib[60]. At his first visit, 
the patient presented with grade 1 nausea and grade 
1 hypertension. Later, he also developed grade 2 rash 
on the back of the legs, corresponding to 18% of the 
body surface area (BSA). In this scenario, manage-
ment of rash includes topical steroids, which may be 
complemented by oral antihistamines. Early referral 
to a dermatologist is advised[59]. The patient contin-
ued combination therapy and started treatment with 
topical steroids, until developing intense grade 3 rash 
on the legs, corresponding to a BSA of 36%. In this 
case, the patient requires management with systemic 
steroids and a dermatological review is indicated[59]. 
Therapy should be put on hold and continued only 
after symptoms have improved. Combination ther-
apy was resumed after symptoms had improved, until 
recurrent grade 3 rash led to permanent discontinu-
ation of first pembrolizumab and later lenvatinib, due 
to tyrosine kinase inhibitor (TKI)-related rash. In some 
practices, TKI may be discontinued prior to ICI due to 
its shorter-acting effects. Steroid treatment may be 
considered if rash persists after TKI discontinuation. 
If rashes improve after treatment discontinuation, 
treatment dose reduction may be considered. When 
evaluating additional treatment options, it is also 
important to keep the patient’s quality of life, which 
may be deeply impacted by skin rashes, in mind.



B2B: BLADDER CANCER SUMMARY

13

B2B: Bladder Cancer Summary

Abbreviations Used in the Text
ADC antibody-drug conjugate
AE adverse event
BCa bladder cancer
BCG bacillus Calmette-Guérin
BSA body surface area 
BSC best supportive care
CI confidence interval
CIS carcinoma in situ
CR complete response
CT computed tomography
DFS disease-free survival
DOR  duration of response
ELISA enzyme-linked immunosorbent assay
FDA U.S. Food and Drug Administration
FGFR fibroblast growth factor receptor
FISH fluorescence in situ hybridization
HR hazard ratio
ICI  immune checkpoint inhibitor
ITT intent-to-treat
LUTS lower urinary tract symptom

MIBC  muscle-invasive bladder cancer
mRNA messenger RNA
NAC neoadjuvant chemotherapy
NBI narrow band imaging
NMIBC non-muscle-invasive bladder cancer
NPV negative predictive value
ORR objective response rate
OS overall survival
PD-L1 programmed death-ligand 1
PFS progression-free survival
PR partial response
RCC renal cell carcinoma
RFS recurrence-free survival
SD stable disease
TKI tyrosine kinase inhibitor
TRAE treatment-related adverse event
TSH thyroid-stimulating hormone
TURB transurethral resection of bladder tumour
UC urothelial carcinoma
UTUC upper tract urothelial carcinoma

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B2B: Bladder Cancer Summary

8. A phase 2b study of UGN-102 for low grade intermediate 
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11. Testing the Addition of an Anti-cancer Drug, 
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B2B: BLADDER CANCER SUMMARY

15

B2B: Bladder Cancer Summary

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B2B: Bladder Cancer Summary

45. A Study of TAR-200 in combination with cetrelimab, 
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