J Urol Oncol > Volume 21(3); 2023 > Article
Yu and Sung: Optimal Management of Bacillus Calmette-Guérin-Refractory Non-Muscle-Invasive Bladder Cancer in 2023


Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) poses a significant clinical challenge, prompting a need for effective treatment options. Although radical cystectomy is a standard approach, it is burdened by high morbidity, mortality, and adverse effects on patients’ quality of life, necessitating the exploration of alternative bladder preservation strategies. This review presents a diverse range of bladder preservation options to improve outcomes in patients with BCG-unresponsive NMIBC. The interventions discussed include intravesical chemotherapy, device-assisted therapy, immunotherapy with checkpoint inhibitors, antibody-drug conjugates, intravesical gene therapy, and combinations of these treatments.


Bacillus Calmette-Guérin (BCG) therapy for bladder cancer is the most efficacious immunotherapeutic intervention employed against human neoplasms [1]. The United States Food and Drug Administration (U.S. FDA) granted approval for this immunotherapy in 1990, marking a historic milestone as the first cancer immunotherapeutic agent to attain such authorization.
In the management of intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC), standard treatment entails intravesical BCG instillation, which effectively reduces the risk of recurrence [2,3]. Furthermore, BCG maintenance therapy significantly decreases the risk of progression [4]. Despite being the cornerstone of NMIBC treatment, a substantial proportion of patients (approximately one-third) do not respond to BCG therapy. Furthermore, more than 50% of those who initially respond subsequently experience recurrence or progression during follow-up [5]. Moreover, local or systemic adverse events occur in approximately 70% of patients, leading to roughly 5% to 9% of patients discontinuing treatment prematurely and not completing the planned BCG course [6,7]. Patients encountering recurrence or progression to muscle-invasive bladder cancer (MIBC) following BCG therapy are considered to have experienced BCG failure. The objectives of this study were to define BCG failure and explore potential treatment approaches for patients who do not respond to BCG therapy.


The concept of BCG failure involves various considerations [8-10]. First, patients with low-grade recurrence during or after BCG treatment are not categorized as cases of BCG failure. Second, the detection of MIBC at any point during the follow-up period is deemed a treatment failure. Third, BCG intolerance refers to severe side effects that hinder further BCG instillation. Finally, the occurrence of high-grade disease following adequate therapy is primarily defined according to Table 1 of the European Association of Urology Guidelines [11].
A particularly important point is that the BCG-unresponsive category includes both BCG-refractory and certain BCG-relapsing tumors. This definition was formulated in collaboration with the U.S. FDA, with a specific focus on facilitating single-arm trials to establish primary evidence of effectiveness in this context. In this definition, adequate BCG treatment is defined as the administration of a minimum of 5 out of 6 doses during the initial induction course, coupled with at least 2 out of 6 doses during the second induction course, or 2 out of 3 doses of maintenance therapy.


Expert committees, along with various clinical guidelines, recommend radical cystectomy as the standard therapeutic approach for BCG-unresponsive NMIBC [11-14]. Delayed cystectomy in patients with NMIBC recurrence following BCG may be associated with unfavorable cancer-specific survival outcomes [15]. Furthermore, in a retrospective study that involved patients who experienced T1 recurrence after BCG therapy, those who underwent radical cystectomy exhibited a lower cancer-related mortality rate (31% vs. 48%) than patients who underwent repeated transurethral resection of the bladder tumor and intravesical BCG therapy [16]. Nonetheless, radical cystectomy is linked to a spectrum of postoperative complications (30%-70%) and mortality risk (approximately 3%) [17-20].
Taking these factors into account, it is imperative to offer thorough counseling to patients, particularly those undergoing radical cystectomy. This approach aims to optimize oncologic outcomes while weighing the relatively elevated risk of morbidity, mortality, and impact on quality of life associated with the procedure. Consequently, bladder preservation strategies employing diverse mechanisms have been extensively explored for patients who decline surgery or are ineligible (Table 2); some of these strategies have shown promising results.


1. Valrubicin

In 1998, valrubicin, a lipid-soluble semisynthetic analog of doxorubicin, was approved by the U.S. FDA for the treatment of BCG-refractory carcinoma in situ (CIS) in patients ineligible for cystectomy due to morbidity and mortality concerns; this approval was supported by data from a pivotal phase 3 study. In this open-label, noncomparative pivotal phase 3 study, 90 patients with recurrent CIS following multiple unsuccessful intravesical therapies, including at least one course of BCG, were treated with 800 mg of intravesical valrubicin for 6 consecutive weeks, resulting in a complete response (CR) rate of 21%, with 7 patients maintaining disease-free status during the median follow-up period of 30 months [21]. A comprehensive evaluation of valrubicin’s efficacy, utilizing updated efficacy data from a pivotal phase 3 trial along with data from a supportive phase 2/3 study, reported that in both studies, the CR rate remained only 18% at the 6-month follow-up, leading to limited further research in this area [22].

2. Gemcitabine

Gemcitabine, an anticancer antimetabolite, blocks DNA synthesis and induces apoptosis in tumor cells through the formation of active metabolites.
Dalbagni et al. [23] investigated the efficacy of intravesical gemcitabine in patients with NMIBC that was refractory or intolerant to intravesical BCG therapy who were unwilling to undergo cystectomy. Two courses of intravesical gemcitabine were administered twice weekly at a dose of 2,000 mg/100 mL for 3 consecutive weeks, with a week of rest between each course. Among the 30 eligible patients, 15 of 30 (50%) achieved CR at the 8-week follow-up, and the 1-year recurrence-free survival rate for patients with CR was 21%.
In a comparative study of mitomycin C (MMC) in patients with a history of previously treated recurrent NMIBC, intravesical gemcitabine demonstrated a higher recurrencefree rate, with an absence of recurrence noted in 39 of 54 patients (72%) compared to 33 of 55 (61%) in the MMC group [24]. Additionally, the incidence of chemical cystitis was significantly lower in the gemcitabine group than in the MMC group (p=0.012), indicating that gemcitabine was less toxic than MMC.
Another study also compared the efficacy of gemcitabine and secondary BCG in the context of initial BCG failure [25]. In this prospective, randomized phase 2 trial, eligible patients with high-risk NMIBC and one failed BCG course were randomly assigned to receive either intravesical gemcitabine or intravesical BCG treatment. Eighty participants, with 40 in each group, were enrolled, and the results revealed a lower disease recurrence rate in the intravesical gemcitabine group (52.5%) than in the intravesical BCG group (87.5%) (p=0.002) and a significantly higher 2-year recurrence-free survival rate in the intravesical gemcitabine group (19%) than in the intravesical BCG group (3%) (p<0.008).
Skinner et al. [26] evaluated the durability of intravesical gemcitabine therapy. Eligible patients with recurrent NMIBC after at least 2 prior courses of BCG were treated with 2 g of gemcitabine in 100 mL normal saline intravesically on a weekly basis for 6 weeks. Subsequently, this regimen continued on a monthly basis for up to 12 months. Out of the 58 enrolled patients, 47 were could be evaluated for their response, and at the initial 3-month evaluation, 47% were disease-free. However, the study found that fewer than 30% of patients had a durable response at 12 months, even with maintenance therapy, with 28% and 21% remaining diseasefree at 1 and 2 years, respectively.
A Cochrane review published in 2021 on intravesical gemcitabine identified 6 relevant randomized trials with a total of 704 patients [27]. The review indicated that a single dose of gemcitabine immediately following surgery was ineffective based on one study. Additionally, gemcitabine exhibited potentially greater activity and lower toxicity than MMC; in comparison to intravesical BCG therapy, it demonstrated comparable effects in patients with intermediate risk, lower efficacy in patients with high risk, and superior outcomes in patients with BCG-refractory disease.

1) Gemcitabine + MMC

Combination therapy has been further investigated to enhance its effectiveness in targeting diverse tumor cells and reducing therapy resistance. In a retrospective review of 47 patients with NMIBC who received 6 weekly treatments of sequential intravesical gemcitabine (1 g) for 90 minutes followed by MMC (40 mg) for an additional 90 minutes, the CR rates at 6 weeks after induction and the 1-year and 2-year recurrence-free survival rates were 68%, 48%, and 38%, respectively, with a median recurrence-free survival of 9 months (range, 1-80 months) [28]. Fourteen out of 47 patients (30%) remained free of recurrence with a median follow-up time of 26 months (range, 6-80 months). Another study identified patients who received sequential weekly instillations of gemcitabine and MMC for 6-8 weeks; 10 out of the enrolled patients (37%) showed no evidence of disease, with a median follow-up duration of 22.1 months [29]. However, the observed outcomes appear to be less effective than those achieved with subsequently explored alternative medications, and no further investigations are currently underway in this regard.

3. Docetaxel

Docetaxel, a microtubule depolymerization inhibitor, exhibits antitumor activity against a broad range of cancers. In 2006, findings from a phase 1 trial evaluating intravesical docetaxel for BCG-refractory NMIBC were reported [30]. The study demonstrated a promising 56% response rate with minimal toxicity in 18 patients who received a single 6-week course of intravesical instillation, following the phase 1 dose escalation protocol.
In a larger cohort of 33 patients with refractory NMIBC receiving salvage intravesical docetaxel therapy, 36% experienced grade 1 or 2 local toxicity, and no cases of grade 3 or 4 local or systemic toxicity were observed [31]. Out of these patients, 61% achieved CR after undergoing 6 weekly induction treatments, as evaluated 4-6 weeks after the instillation.
Moreover, the long-term outcomes of salvage intravesical docetaxel treatment were reported in 54 patients with BCG refractory NMIBC, revealing a 59% rate of initial CR following 6 weekly instillations [32]. Among initial responders, those who received additional monthly maintenance treatments experienced a longer median time to recurrence (39.3 months vs. 19.0 months), and the 1- and 3-year recurrence-free survival rates for the entire cohort were 40% and 25%, respectively, suggesting that adding maintenance treatments may prolong recurrence-free survival.
Research on the combination of docetaxel and gemcitabine for potential therapeutic applications is ongoing.

1) Gemcitabine and docetaxel

In 2015, Steinberg et al. [33] introduced the concept of sequential gemcitabine and docetaxel treatment. Patients received 6 weekly instillations of gemcitabine (1 g in 50 mL of sterile water) for 60 minutes, followed immediately by docetaxel (37.5 mg in 50 mL of saline) for an additional 60 minutes. The treatment success rates were 66% at the first surveillance, 54% at 1 year, and 34% at 2 years after initiating induction.
Subsequent retrospective studies explored the outcomes of 59 patients who received complete gemcitabine/docetaxel treatment for NMIBC [34]. Overall, disease-free survival rates were 49% at 1 year and 29% at 2 years. For patients in whom multiple induction courses of BCG had failed, the overall disease-free survival rates were 48% at 1 year and 32% at 2 years. Moreover, among patients eligible for maintenance therapy who received ≥1 induction courses of BCG, disease-free survival rates at 1 year were 42% for observed patients and 81% for those receiving maintenance therapy, while at 2 years, they were 34% for observed patients and 59% for those receiving maintenance therapy. In another study involving 276 patients, the 1- and 2-year recurrencefree survival rates were 60% and 46%, respectively, and the high-grade recurrence-free survival rates were 65% and 52%, respectively [35].
Further evaluations are necessary because no prospective studies have been conducted to date. Currently, although there appear to be no ongoing studies specifically investigating the combination of gemcitabine and docetaxel alone for patients unresponsive to BCG, there are ongoing prospective clinical trials combining gemcitabine and docetaxel with immunotherapy for BCG-unresponsive cases. Additionally, other studies are exploring the use of gemcitabine and docetaxel in patients who have not previously received BCG treatment.

4. Paclitaxel

Nanoparticle albumin-bound (nab)-paclitaxel is a modified taxane with improved solubility and lower toxicity than other taxanes that exerts anticancer effects through tubulin polymerization, microtubule stabilization, cell cycle arrest, and apoptosis induction.
A single-center, single-arm, phase 2 trial investigated the use of intravesical nab-paclitaxel (500 mg/100 mL) in patients with recurrent NMIBC after failure of at least one prior regimen of intravesical BCG [36]. Among the 28 enrolled patients, 35.7% exhibited CR at 6 weeks after initial treatment. Furthermore, after 1 year, all of these responses continued to be sustained with the aid of maintenance therapy. Treatment-related adverse events were limited to grade 1 or 2, indicating that intravesical nab-paclitaxel demonstrated minimal toxicity and a promising response rate in heavily pretreated patients with NMIBC and prior BCG failure.
In another phase 2 trial of intravesical nab-paclitaxel involving 28 patients with NMIBC after prior intravesical BCG failure, 36% of patients achieved CR at 6 weeks following the final instillation, with a recurrence-free survival rate of 18% at a median follow-up of 41 months (range, 5-76 months) [37].
However, the routine use of this agent still awaits independent validation. A phase 3, single-arm study (NCT 05024773) evaluating the efficacy and safety of ONCOFIDP-B (paclitaxel-hyaluronic acid conjugate) administered intravesically to patients with BCG-unresponsive CIS with or without Ta-T1 papillary disease is currently recruiting patients, and the estimated primary completion date is November 2025.


1. Device-Assisted Instillations of MMC

The superiority of gemcitabine over standard MMC in a head-to-head randomized controlled trial for BCG failure [24] implies that standard MMC may not be a suitable treatment option following BCG failure. As an alternative, methods for enhancing MMC efficacy using devices have been developed to achieve better outcomes.

1) Chemohyperthermia

Arends et al. [38] compared the efficacy of chemohypothermia (CHT) using MMC with BCG as adjuvant treatments for intermediate- and high-risk NMIBC in patients without a history of BCG therapy. Among the 184 patients included, only 10 had a history of BCG treatment. The 24-month intention-to-treat recurrence-free survival rate was 78.1% in the CHT group compared to 64.8% in the BCG group (p=0.08). The 24-month recurrence-free survival rates in the per-protocol analysis were 81.8% in the CHT group and 64.8% in the BCG group (p=0.02). Both groups had progression rates of less than 2%, and no new safety concerns were identified. However, the study’s premature closure resulted in an underpowered analysis, warranting caution when interpreting the results.
In a recent study comparing the radiofrequency-induced thermo-chemotherapy effect (RITE) with institutional standard second-line therapy (control) in patients with NMIBC experiencing recurrence following induction/maintenance BCG, no significant difference was observed in disease-free survival time between the treatment arms [39]. Additionally, a subgroup analysis of patients with CIS with or without papillary disease, demonstrated that disease-free survival time was significantly lower in the RITE group than in the control group (hazard radio, 2.06; 95% confidence interval [CI], 1.17-3.62; p=0.01).

2) Electromotive drug administration

Electromotive MMC demonstrated superior transport rates compared to passive transport. In a clinical trial involving 108 patients with high-risk NMIBC, electromotive MMC demonstrated superior CR rates at 3 and 6 months compared to passive MMC (53% vs. 28%, p=0.036 and 58% vs. 31%, p=0.012, respectively), and a longer median time to recurrence (35 months vs. 19.5 months, p=0.013) [40]. Peak plasma MMC levels were significantly higher with electromotive MMC, indicating increased bladder content absorption.
In a prospective, single-center, single-arm phase 2 study involving 26 consecutive patients with BCG-refractory highgrade NMIBC, with a 3-year follow-up, the electromotive drug administration (EMDA®)-MMC treatment—comprising 40 mg of MMC diluted in 100 mL of sterile water retained in the bladder for 30 minutes with 20 mA pulsed electric current—demonstrated efficacy in preserving the native bladder in 61.5% of patients. Additionally, it showed disease-free rates of 75%, 71.4%, 50%, and 25% for TNM classifications of TaG3, T1G3, Cis, TaT1G3 + Cis, respectively [41]. However, adverse events, including hypersensitivity to MMC in 11.5% of patients and local side effects in 26.1% of patients, were reported during the study. The encouraging outcomes observed in BCG-refractory patients clearly warrant further research to assess the efficacy and safety of EMDA-MMC treatment in comparison to existing therapies.

2. Photodynamic Therapy

In 2023, interim findings were released, detailing the outcomes of a phase 2 clinical study on intravesical photodynamic therapy for patients with BCG-unresponsive CIS with or without papillary disease (NCT03945162) [42]. The study involved intravesical instillation of the photosensitizer TLD-1433 (0.70 mg/cm2), followed by activation using a 520-nm intravesical laser (Study Device TLC-3200) and consequently delivering a total of 90 J/cm2 of laser light under general anesthesia. Among the 45 enrolled patients, the data showed CR rates of 50% at 90 days, 35% at 360 days, and 21% at 450 days. Eight serious adverse events were identified in the study. The study is currently ongoing, with recruitment in progress, and the estimated completion date is December 2025.


Immunotherapy holds promise for patients with NMIBC due to the higher mutational load of tumors, which triggers an immune response and results in improved efficacy for immune checkpoint inhibitors [43]. Furthermore, BCG infection induces programmed death-ligand 1 (PD-L1) expression in regulatory T cells, making combination or sequential checkpoint inhibitor therapy a potential strategy for patients unresponsive to BCG [44].
Numerous ongoing clinical trials are investigating various immunotherapeutic agents and their combinations with other therapeutic options. Presentation of their results is currently in progress.

1. Intravesical Immunotherapy

Immunotherapy is currently being investigated more extensively through systemic (intravenous) administration than through intravesical administration. Two ongoing small single-group assignment studies—NCT02808143 (phase 1) assessing intravesical pembrolizumab with concurrent BCG for high-grade disease or BCG-refractory and NCT03759496 (phase 2) assessing intravesical durvalumab in patients with high-grade disease or BCG nonresponsiveness—are actively recruiting patients to assess the tolerance and efficacy of these treatments.

2. Systemic Immunotherapy

1) Pembrolizumab

A recent publication detailing the KEYNOTE-057 (NCT 02625961) trial described the assessment of pembrolizumab, a PD-1 inhibitor, to determine its efficacy and safety in managing high-risk NMIBC that had proven unresponsive to BCG therapy [45]. Conducted as an open-label, singlearm, multicenter, phase 2 study, pembrolizumab was administered intravenously at 200 mg every 3 weeks for a maximum of 24 months or until specified endpoints were reached. The data revealed a notable CR rate (39 patients; 41%; 95% CI, 30.7%-51.1%) at 3 months among the cohort of 96 patients with BCG-unresponsive CIS with or without papillary tumors. The median duration of CR was 16.2 months (95% CI, 6.4-36.2 months), and 46% (18 patients) of initial responders had a CR lasting for 12 months or longer. Grade 3 or 4 treatment-related adverse events occurred in 13% of the participants, with arthralgia affecting 2% and hyponatremia affecting 3%. Additionally, 8% of the patients experienced serious treatment-related adverse events. Based on these findings, pembrolizumab was approved by the FDA in 2020. Additionally, a recent analysis of KEYNOTE-057 Cohort B, which focused exclusively on patients with papillary tumors without concomitant CIS, observed that 43.5% of patients remained disease-free 1 year after initiating treatment [46].

2) Atezolizumab

The results of a single-arm phase 2 registration trial (SWOG S1605; NCT 02844816) investigating the efficacy and safety of atezolizumab, an anti-PD-L1 agent, in patients with BCG-unresponsive high-risk NMIBC were reported in 2020 [47]. The study aimed to enroll 135 eligible patients who were ineligible for or declined radical cystectomy, and the analyzed subset comprised 73 patients with CIS with or without concomitant Ta/T1 tumors. At 3 and 6 months, CR was observed in 41.1% and 26.0% of the patients with CIS, respectively. Treatment-related adverse events were reported in 83.6% of the patients, with the most common being fatigue, pruritus, hypothyroidism, and nausea. Grade 3-5 adverse events occurred in 12.3% of the patients, and one treatment-related death due to myasthenia gravis with respiratory failure and sepsis was reported.

3) Durvalumab

According to interim data reported in 2023 from multicenter phase 1/2 trial (ADAPT-BLADDER; NCT03317158), the safety and preliminary efficacy of anti-PD-L1 directed therapy with durvalumab (D), either alone or in combination with intravesical BCG (durvalumab + BCG) or external beam radiation therapy (durvalumab + EBRT), were assessed in patients with BCG-unresponsive NMIBC [48]. The patients received 1,120 mg of durvalumab intravenously every 3 weeks for 8 cycles. The combination therapies demonstrated encouraging preliminary efficacy, with a 3-month CR observed in 64% of all patients. The rates varied within the durvalumab alone, durvalumab + BCG, and durvalumab + EBRT subgroups (33%, 85%, and 50%, respectively). At the 12-month mark, CR rates were achieved in 46% of all patients, and notably in 73% of the durvalumab + BCG patients and 33% of the durvalumab + EBRT patients. Importantly, one patient in the durvalumab + EBRT cohort experienced a grade 3 dose-limiting toxicity event of autoimmune hepatitis, which was the only doselimiting toxicity event reported in the study. This study is currently ongoing and actively recruiting participants, with an estimated completion date of December 31, 2025.

4) Nivolumab

Currently, 2 major clinical trials are in progress in the field of NMIBC immunotherapy. CheckMate 9UT (NCT 03519256) is a phase 2, randomized open-label study investigating the safety and efficacy of nivolumab (anti-PD-1) alone or in combination with linrodostat mesylate or intravesical BCG in patients with BCG-unresponsive highrisk NMIBC. Another trial (NCT04149574) is a phase 3, randomized, double-blind study comparing nivolumab in combination with intravesical BCG to standard-of-care BCG alone in participants with high-risk NMIBC that persisted or recurred after BCG treatment.


1. Vicinium (Oportuzumab Monatox, VB4-845)

Vicinium is a recombinant fusion protein comprising an epithelial cell adhesion molecule-specific antibody fragment linked to a variant of Pseudomonas exotoxin A. This potent inhibitor of protein synthesis leads to tumor cell death, resulting in the display of immunogenic cell death signals and neo-antigens that promote adaptive T-cell mediated antitumor responses.
In a phase 2 study, the efficacy and tolerability of Vicinium were evaluated in 46 patients with BCG-refractory CIS [49]. Patients received one induction cycle of 6 or 12 weekly intravesical Vicinium instillations of 30 mg, followed by up to 3 maintenance cycles every 3 months. Notably, 20 patients (44%) achieved CR, and the most common adverse events were mild-to-moderate reversible bladder symptoms.
In the phase 3 VISTA study (NCT02449239), 89 patients with CIS or papillary disease were treated with Vicinium. Among the patients with evaluable CIS, a CR rate of 40% was observed at the 3-month mark, with a median duration of response of 9.4 months [50]. The recurrence-free rates for the patients with evaluable papillary were 71%, 58%, 50%, and 37% at 3, 6, 12, and 24 months, respectively.
Although Vicinium showed clinically favorable antitumor activity and was well tolerated in this phase 3 study, its development has been voluntarily discontinued since 2022, following the FDA’s decision of non-approval.

2. N-803 (IL-15 Superagonist)

N-803 is an innovative mutant interleukin (IL)-15-based immunostimulatory fusion protein complex (IL15RaFc) that selectively stimulates the proliferation and activation of natural killer cells and CD8+ T cells while sparing regulatory T cells. According to the results of an open-label, multicenter study (QUILT 3.032; NCT03022825) involving 160 patients with BCG-unresponsive high-grade NMIBC (83 with CIS and 77 with papillary disease) treated with an intravesical mixture of N-803 and BCG, the CR rate in patients with CIS was 71% (59 out of 83), with responders showing a median CR duration lasting 24.1 months [51]. Cystectomy was avoided by 91% of patients with CIS, and the 24-month bladder cancer-specific progression-free survival rate was 96% (defined as progression to MIBC). In patients with papillary disease, the 12-month disease-free survival rate was 57%, the 24-month disease-free survival rate was 48%, and 95% of these patients avoided cystectomy. When comparing N-803 alone with BCG plus N-803, the combination therapy demonstrated greater effectiveness [52]. Researchers suggested that the efficacy and safety profile of N-803 plus BCG combination therapy may surpass those of other available intravesical and systemic treatment options for BCG-unresponsive NMIBC.
However, in May 2023, the approval decision for N-803 was postponed by FDA, with the agency requesting additional data and a safety update, prompting keen attention to both the manufacturer’s response and the FDA’s subsequent actions.


1. Adstiladrin (Nadofaragene Firadenovec [rAd-IFNα2b/Syn3])

Adstiladrin (Nadofaragene firadenovec [rAd-IFNα2b/Syn3]) is a replication-deficient recombinant adenovirus vector carrying the human IFN-α2b gene. Upon intravesical administration, rAd-IFN enters the bladder epithelium, prompting the synthesis and expression of significant amounts of the IFN-α2b protein.
A phase 3 clinical trial (NCT02773849) conducted in patients with BCG-unresponsive NMIBC aimed to evaluate the efficacy of intravesical Adstiladrin [53]. A total of 157 patients were enrolled and treated with a single intravesical dose of the drug, with repeated dosing at 3, 6, and 9 months provided there was no high-grade recurrence. Data reported in 2020 revealed that among 103 patients with CIS (with or without a high-grade Ta or T1 tumor), 53.4% achieved CR within 3 months of the first dose, and this response was sustained in 45.5% of the patients at 12 months. The most common grade 3-4 drug-related adverse event was micturition urgency; no treatment-related deaths occurred.
Adstiladrin, with prolonged exposure to a therapeutic agent compared to conventional instillation, demonstrated clinical efficacy and safety in patients with BCG-unresponsive NMIBC. Based on a positive phase 3 trial (NCT02773849), Adstiladrin was approved by the FDA in December 2022 for the treatment of high-risk BCG-unresponsive NMIBC in adult patients with CIS with or without papillary tumors.

2. CG0070

The first-in-human phase 1 study of CG0070, a granulocyte-macrophage colony-stimulating factor-expressing oncolytic adenovirus, published in 2012, reported that intravesical CG0070 demonstrated a tolerable safety profile and exhibited anti-bladder cancer activity [54].
The interim results of an open-label, single-arm, phase 2 multicenter study (BOND2; NCT02365818) evaluating the safety and efficacy of CG0070 in patients with BCGunresponsive NMIBC were reported in 2018 [55]. Out of 45 patients with residual high-grade Ta, T1, or CIS ± Ta/T1, the overall 6-month CR rate was 47%. The CR rate for pure CIS was 58%, that of CIS ± Ta/T1 was 50%, and that of pure Ta/T1 was 33%. The treatment was generally well tolerated, with urinary bladder spasms, hematuria, dysuria, and urgency reported as main treatment-related adverse events at 6 months. Immunological-treatment-related adverse events included flu-like symptoms and fatigue. No grade IV or V treatment-related adverse events were observed. The study demonstrated a particularly strong response and limited progression in patients with pure CIS.
An ongoing phase 3 clinical trial (BOND-003; NCT 04452591) aims to validate the clinical activity of CG0070 in patients with BCG-unresponsive NMIBC.


Various treatment modalities and combinations are currently being evaluated in clinical trials (Table 3).


BCG-unresponsive NMIBC, which represents an unmet clinical need, poses a substantial challenge for both clinicians and patients. Although radical cystectomy remains a standard treatment option, its association with high morbidity, mortality, and impact on the patients’ quality of life necessitates the exploration of various bladder preservation strategies. Currently, FDA-approved treatments for BCG-unresponsive NMIBC include intravesical valrubicin, Adstiladrin, and systemic pembrolizumab, each of which has its unique advantages and disadvantages (Table 4). Ongoing research holds promise for the future, as potential avenues include combination therapies such as intravesical chemotherapy and novel immunotherapy utilizing checkpoint inhibitors, as well as intravesical gene therapy using viruses.
The focus of this review was to present a wide range of treatment options, including both established and experimental approaches, that aim to improve patient outcomes in cases of BCG-unresponsive NMIBC. Patients should be informed about the off-label status of certain regimens and the substantial risks associated with recurrence and disease progression. These factors may necessitate contemplation of radical cystectomy.
Considering the diversity of options available for bladder preservation, the importance of tailoring treatment to individual patients is underscored. This approach ensures effective outcomes while mitigating the risks associated with radical cystectomy.


Conflicts of Interest

The authors have nothing to disclose.


This study received no specific grant from any funding agency in the public, commercial, or not-for- profit sectors.

Author Contribution

Conceptualization: JY, HHS; Data curation: JY, HHS; Formal analysis: JY, HHS; Methodology: JY, HHS; Project administration: JY, HHS; Visualization: JY, HHS; Writing - original draft: JY, HHS; Writing - review & editing: JY, HHS.

Table 1.
Classifying high-grade recurrence during or after BCG treatment
BCG-refractory tumor
1. If T1 HG/G3 tumor is present at 3 months
2. If Ta HG/G3 tumor is present after 3 months and/or at 6 months, after either reinduction or first course of maintenance
3. If CIS (without concomitant papillary tumor) is present at 3 months and persists at 6 months after either reinduction or first course of maintenance. If patients with CIS present at 3 months, an additional BCG course can achieve a complete response in >50% of cases
4. If HG tumor appears during BCG maintenance therapy
BCG-relapsing tumor
Recurrence of HG/G3 tumor after completion of BCG maintenance, despite an initial response
BCG-unresponsive tumor
BCG-unresponsive tumors include all BCG refractory tumors and those who develop T1/Ta HG recurrence within 6 months of completion of adequate BCG exposure or develop
CIS within 12 months of completion of adequate BCG exposure

BCG, Bacillus Calmette-Guérin; CIS, carcinoma in situ ; HG, high grade.

Table 2.
Mechanisms of therapeutic agents for BCG-unresponsive NMIBC
Variable Route of administration FDA approval* Mechanism of action
Intravesical chemotherapy
Valrubicin Intravesical O Inhibiting nucleoside incorporation, chromosomal damage, G2 cell cycle arrest, interfering DNA breaking-resealing function
Gemcitabine Intravesical - Blocking DNA synthesis and inducing apoptosis in tumor cells through the formation of active metabolites
Docetaxel Intravesical - Prohibiting cancer cell division by promoting assembly and blocking disassembly of microtubules
Paclitaxel Intravesical -
Photodynamic therapy Intravesical - Photosensitizers activated by laser light generate reactive oxygen species, triggering apoptosis and necrosis in cancer cells
Immune checkpoint inhibitors Intravesical Releasing PD-L1/PD-1 mediated inhibition of antitumor immune response of T cell
Pembrolizumab Intravesical O (intravenous) PD-1 blocking antibody
Nivolumab Intravenous -
Atezolizumab Intravenous - PD-L1 blocking antibody
Durvalumab Intravesical -
Antibody-drug conjugates
Vicinium Intravesical - Binding to EpCAM receptors on tumor cells, promoting internalization of the Vicinium toxin and disrupting protein synthesis
N-803 Intravesical - Promoting natural killer and T-cell proliferation, enhancing immunological responses in combination with BCG or other checkpoint inhibitors
Intravesical gene therapy
Adstiladrin Intravesical O Introducing interferon alfa-2b gene into bladder wall cells, promoting production of high levels of interferon alfa-2b protein, harnessing innate anticancer defenses
CG0070 Intravesical GM-CSF-expressing oncolytic adenovirus, inducing tumor cell lysis and immunogenic cell death by intracellular replication, releasing tumor-derived antigens and GM-CSF to initiate a systemic antitumor immune response

BCG, Bacillus Calmette-Guérin; NMIBC, non-muscle-invasive bladder cancer; FDA, Food and Drug Administration; PD-L1, programmed death-ligand 1; PD-1, programmed death receptor-1; EpCAM, epithelial cell adhesion molecule; GM-CSF, granulocyte-macrophage colony-stimulating factor.

* FDA approval granted for the treatment indication in patients with BCG-unresponsive NMIBC.

Table 3.
Current investigational clinical trials on therapeutic agents for BCG-unresponsive NMIBC
Trial number Study title Intervention Status/estimated study completion date
NCT04172675 A Randomized Phase 2 Study of Erdafitinib Versus Investigator Choice of Intravesical Chemotherapy in Subjects Who Received Bacillus Calmette-Guérin (BCG) and Recurred With High Risk Non-Muscle- Invasive Bladder Cancer (NMIBC) and FGFR Mutations or Fusions Oral Erdafitinib vs. intravesical chemotherapy (gemcitabine or mitomycin C) Recruiting/March 29, 2024
NCT04164082 Phase II Trial of Intravesical Gemcitabine and MK-3475 (Pembrolizumab) in the Treatment of Patients With BCG-Unresponsive Non-Muscle Invasive Bladder Cancer Intravesical gemcitabine plus intravenous pembrolizumab Recruiting/March 31, 2024
NCT04106115 A Phase Ib/II Study to Assess the Safety and Activity of DURvalumab (MEDI4736) in Combination With S-488210/S-488211 vAccine in Non- muscle Invasive Bladder CancEr (DURANCE) Intravenous durvalumab plus S-488210/S-488211 (5-peptide cancer vaccine) Recruiting/May 31, 2029
NCT03950362 Bladder PREserVation by RadioTherapy and Immunotherapy in BCG Unresponsive Non-muscle Invasive Bladder Cancer (PREVERT) Intravenous avelumab plus radiation Not yet recruiting/June 15, 2024
NCT04738630 A Single-arm, Open-Label, Multicenter, Phase II Clinical Study of HX008 in Subjects With BCG-Unresponsive Non-muscle Invasive Bladder Cancer Intravenous HX008 (PD-1 antibody) Recruiting/December 1, 2023
NCT04752722 A Phase 1/2 Study of EG-70 as an Intravesical Administration to Patients With BCG Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC) and High-Risk NMIBC Patients Who Are BCG Naïve or Received Incomplete BCG Treatment Intravesical EG-70 (nonviral gene therapy encoding 2 RIG-1 agonists) Recruiting/May 2027
NCT04387461 A Phase 2, Single Arm Study of CG0070 Combined With Pembrolizumab in Patients With Non Muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guerin (BCG) Intravesical CG0070 plus intravenous pembrolizumab Active, not recruiting/June 2023
NCT04640623 Phase 2b Clinical Study Evaluating Efficacy and Safety of TAR-200 in Combination With Cetrelimab, TAR-200 Alone, or Cetrelimab Alone in Participants With High-Risk Non-Muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Intravesical Bacillus Calmette-Guérin (BCG) Who Are Ineligible for or Elected Not to Undergo Radical Cystectomy (SunRISe-1) Intravenous cetrelimab (PD-1 inhibitor), intravesical TAR-200 (continuous intravesical release gemcitabine) or combination Recruiting/July 2, 2027
NCT02202772 A Phase I Trial for the Use of Intravesical Cabazitaxel, Gemcitabine, and Cisplatin (CGC) in the Treatment of BCG-Refractory Non-muscle Invasive Urothelial Carcinoma of the Bladder Cancer Intravesical cabazitaxel, gemcitabine and cisplatin Recruiting/December 2024

BCG, Bacillus Calmette-Guérin; NMIBC, non-muscle-invasive bladder cancer.

Table 4.
Pros and cons of FDA-approved agents
Agent Pros Cons
Intravesical valrubicin Relatively long history of use Relatively low efficacy and sustainability
Irritative symptoms of bladder
Intravesical Adstiladrin Fewer instillation Risk for disseminated adenovirus infection (contraindicated to immunocompromised patients)
Prolonged exposure of therapeutic agent
Relatively high efficacy and sustainability Irritative symptoms of bladder
Intravenous pembrolizumab No catheterization Systemic and immune-related adverse effect
Relatively high efficacy and sustainability Variations in response based on tumor PD-L1 expression

FDA, Food and Drug Administration; PD-L1, programmed death-ligand 1.


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