The current and future role of systemic therapy in non–muscle‐invasive bladder cancer

Abstract

Non–muscle‐invasive bladder cancer (NMIBC) categorizes early‐stage urothelial carcinoma that has not invaded the bladder's muscle layer. Although it is initially treatable with transurethral resection, NMIBC has a high risk of recurrence and progression, which necessitates prolonged surveillance and intravesical therapies. Intravesical bacillus Calmette–Guérin (BCG), originally developed as a tuberculosis vaccine, has proven effective in reducing recurrence and delaying progression in NMIBC. Notably, BCG immunotherapy was among the first treatments to demonstrate that activating the immune system could control localized urothelial cancer. Although there has been recent growth in novel intravesical therapies for patients with BCG‐unresponsive disease, options remain limited, and radical cystectomy is still frequently performed. Recent advances in systemic therapies, especially immunotherapies targeting the programmed cell death protein 1/programmed death ligand 1 pathway, have now affected NMIBC, with pembrolizumab receiving regulatory approval. This development has spurred numerous clinical trials investigating systemic therapeutic agents in NMIBC alone or in combination with other modalities such as intravesical therapy or radiation to improve outcomes. To understand the current landscape in this clinical space, a systematic review of systemic therapy in NMIBC was performed. Current data and ongoing studies that use systemic agents to treat this disease are presented. Despite recent progress in this domain, there remains a substantial need for more effective treatments with fewer toxicities for NMIBC. Future trials will be essential for optimizing these therapies and improving patient outcomes.

Short abstract

Current evidence and ongoing trials investigating systemic therapies in high‐risk non–muscle‐invasive bladder cancer are presented.

INTRODUCTION

Bladder cancer ranks as the ninth most commonly diagnosed cancer worldwide, with 614,000 new diagnoses and 220,000 deaths reported in 2022. ¹ Non–muscle‐invasive bladder cancer (NMIBC) encompasses the early stages of urothelial carcinoma without invasion into the muscularis propria, or muscle layer of the bladder wall. These cancers are considered curable with cystoscopic interventions, although they can recur with high frequency or progress to more advanced disease. Thus, they require long‐term surveillance, and high‐risk patients have historically been treated with intravesical therapies. ²

The development of bacillus Calmette–Guérin (BCG) for the treatment of NMIBC began in 1976, and marked a significant milestone in bladder cancer treatment. BCG stimulates the immune system to attack cancer cells within the bladder and has become the gold standard for treating NMIBC, particularly for intermediate‐ and high‐risk NMIBC, which has significantly reduced recurrence and progression to muscle‐invasive bladder cancer (MIBC). ³ , ⁴ Although this therapy is administered locally in the bladder, its mechanism of efficacy validated the potential to use the systemic immune response against bladder cancer.

BCG stimulates a robust local and some systemic immune response that targets tumor cells, which contributes to long‐term protection against recurrence. ⁵ Despite its effectiveness in reducing recurrence, only 16%–30% of patients complete the full induction and maintenance courses because of the demanding schedule and side effects. ⁶ Furthermore, 30%–50% of patients experience a recurrence after an adequate BCG therapy. BCG‐unresponsive disease poses a significant clinical challenge that often leads to radical cystectomy (RC). ^{7 , 8 , 9} Because of the scarcity of effective treatments for this subgroup and the worldwide BCG shortage, ¹⁰ there has been a rapid surge in the clinical development of various therapeutic options in this context, including both intravesical and systemic agents. ¹¹ , ¹²

Systemic therapy for NMIBC presents many opportunities as well as challenges. ¹³ Cancer, even at an early stage, is a systemic disease, with targetable vulnerabilities that can be addressed with an intravenous or oral therapeutic approach. For example, mismatch repair–deficient colorectal cancer has recently been observed to be highly sensitive to systemic immunotherapy. ¹⁴ In NMIBC, systemic therapies are under active clinical investigation. The first systemic therapy approved for BCG‐unresponsive NMIBC was pembrolizumab, which targets the PD‐1 (programmed cell death protein 1)/PD‐L1 (programmed death ligand 1) pathway. ¹⁵ Nonetheless, challenges of modest activity and toxicities remain with this approach. ¹³ Herein, we review the current landscape of published data and future directions for systemic therapy in early‐stage bladder cancer (Table 1).

TABLE 1.

Systemic drugs for high‐risk non–muscle‐invasive bladder cancer.

Drug	Drug class	Mechanism of action	Route of administration
Pembrolizumab	Anti–PD‐1 monoclonal antibody	Blocks the PD‐1 receptor on T cells to prevent interaction with PD‐L1/PD‐L2, which restores T‐cell activity against tumor cells	Intravenous
Atezolizumab	Anti–PD‐L1 monoclonal antibody	Binds PD‐L1 on tumor and immune cells, which prevents its interaction with PD‐1 and enhances T cell activation	Intravenous
Erdafitinib	FGFR tyrosine kinase inhibitor	Inhibits FGFR1–FGFR4 signaling pathways, which are involved in cell proliferation and survival in FGFR‐altered tumors	Oral
Avelumab	Anti–PD‐L1 monoclonal antibody	Binds PD‐L1 on tumor and immune cells, which prevents its interaction with PD‐1 and enhances T cell activation	Intravenous
Durvalumab	Anti–PD‐L1 monoclonal antibody	Binds PD‐L1 on tumor and immune cells, which prevents its interaction with PD‐1 and enhances T cell activation	Intravenous
Sasanlimab	Anti–PD‐1 monoclonal antibody	Blocks the PD‐1 receptor on T cells to prevent interaction with PD‐L1/PD‐L2, which restores T‐cell activity against tumor cells	Subcutaneous

Abbreviations: FGFR, fibroblast growth factor receptor; PD, programmed cell death; PD‐L, programmed death ligand.

METHODS

Our investigation involved a comprehensive review of the ClinicalTrials.gov and PubMed databases to identify key ongoing and completed clinical trials focused on systemic agents in the context of NMIBC between January 2019 and June 2024. The search strategy used a variety of relevant terms, which included “bladder cancer,” “non‐muscle invasive bladder cancer,” “BCG‐unresponsive non‐muscle invasive bladder cancer,” “BCG‐naïve non‐muscle invasive bladder cancer,” “BCG‐refractory non‐muscle invasive bladder cancer,” “BCG failure non‐muscle invasive bladder cancer,” “systemic therapy,” “systemic immunotherapy,” as well as “systemic targeted therapy.” Specific emphasis was placed on ongoing trials that assess both oncological outcomes and adverse events related to systemic therapy in NMIBC. Additionally, scrutiny was applied to multiarm trials, which compare systemic agents and other therapies for NMIBC.

RESULTS

Published trials of systemic therapy for NMIBC (Table 2)

TABLE 2.

Published and ongoing clinical trials evaluating systemic therapies in high‐risk non–muscle‐invasive bladder cancer.

Study	Study ID	Study phase, design	Patients, No.	Study cohorts	Treatment arms	End points
Published trials of systemic therapy for NMIBC							Study results/approval status
KEYNOTE‐057 cohort A	NCT02625961	2, single arm	101	BCG‐unresponsive CIS, with/without papillary tumors	Pembrolizumab 200 mg every 3 weeks for up to 24 months	CR at 3 months	FDA approved in January 2020
KEYNOTE‐057 cohort B	NCT02625961	2, single arm	132	BCG‐unresponsive HR NMIBC papillary tumors	Pembrolizumab 200 mg every 3 weeks for up to 24 months	HR NMIBC DFS at 12 months	The study achieved the 30% RFS at 12 months criteria set by the IBCG; however, it did not lead to FDA approval
SWOG S1605	NCT02844816	2, single arm	129	BCG‐unresponsive HR NMIBC	Atezolizumab 1200 mg every 3 weeks for up to 17 cycles	Pathological CR at 6 months for patients with CIS, and EFS at 18 months for all patients	Negative trial
THOR‐2 cohort 1	NCT04172675	2, randomized trial (2:1)	73	BCG‐treated HR NMIBC papillary tumors with FGFR alterations	Daily oral erdafitinib 6 mg for up to 2 years versus intravesical chemotherapy (mitomycin C or gemcitabine) (induction + maintenance)	RFS	Positive trial results; however, it did not lead to FDA approval
Ongoing trials of systemic therapy for NMIBC							Primary completion date	Estimated completion date
KEYNOTE‐676	NCT03711032	3, RCT	1405	A: adequate BCG in HR NMIBC induction B: BCG‐naive HR NMIBC	A1: BCG (induction + maintenance) + pembrolizumab A2: BCG (induction + maintenance) B1: BCG (induction + reduced maintenance) + pembrolizumab B2: BCG (induction + full maintenance) + pembrolizumab B3: BCG (induction + maintenance)	A: CR at 3.5 years B: EFS at 5 years	December 31, 2025	October 12, 2028
—	NCT04164082	2, single arm	161	BCG‐unresponsive HR NMIBC	Intravesical gemcitabine + pembrolizumab	CR for CIS at 6 months, and EFS for all patients at 18 months	March 31, 2025	March 31, 2025
ALBAN	NCT03799835	3, RCT	516	BCG‐naive HR NMIBC	A: BCG (induction + maintenance) for 1 year B: BCG (induction + maintenance) + atezolizumab for 1 year	RFS at 2 years	October 2024	October 2028
PREVERT	NCT03950362	2, single arm	67	BCG‐unresponsive HR NMIBC	Whole‐bladder radiotherapy (60–66 Gy) + avelumab	HR RFS at 1 year	June 15, 2023	June 15, 2024
POTOMAC	NCT03528694	3, RCT	1018	BCG‐naive HR NMIBC	1: BCG (induction + maintenance) 2: BCG (induction + maintenance) + durvalumab 3: BCG (induction only) + durvalumab	DFS at 4 years	October 31, 2024	September 30, 2025
ADAPT Bladder	NCT03317158	1/2, multiarm	55	BCG‐naive/relapsing/unresponsive HR NMIBC	1: durvalumab 2: durvalumab + BCG 3: durvalumab + radiotherapy 4: durvalumab + intravesical gemcitabine/docetaxel	Phase 1: safety Phase 2: CR	December 31, 2024	December 31, 2025
CREST	NCT04165317	3, RCT	1000	BCG‐naive HR NMIBC	A: sasanlimab + BCG (induction + maintenance) B: sasanlimab (induction only) C: BCG (induction + maintenance)	EFS at 5 years	December 2, 2024	December 2, 2026

Abbreviations: BCG, bacillus Calmette–Guérin; CIS, carcinoma in situ; CR, complete response; DFS, disease‐free survival; EFS, event‐free survival; FDA, Food and Drug Administration; FGFR, fibroblast growth factor receptor; HR, high‐risk; IBCG, International Bladder Cancer Group; NMIBC, non–muscle‐invasive bladder cancer; RCT, randomized controlled trial; RFS, recurrence‐free survival.

KEYNOTE‐057 trial cohort A: BCG‐unresponsive carcinoma in situ ± papillary tumors

The KEYNOTE‐057 trial marked the first breakthrough of systemic immunotherapy in the realm of high‐risk NMIBC with the approval of pembrolizumab by the Food and Drug Administration in January 2020 for the treatment of BCG‐unresponsive carcinoma in situ (CIS) with/without Ta/T1 papillary tumors in patients who were ineligible or unwilling to undergo RC. ¹⁵ One hundred and one patients were enrolled between December 2015 and April 2018 to receive intravenous pembrolizumab 200 mg every 3 weeks for up to 24 months or until centrally confirmed disease persistence, recurrence or progression, unacceptable toxicity, or withdrawal of consent. Five patients did not meet the definition for BCG‐unresponsive NMIBC, and were excluded; hence, the efficacy analysis included 96 patients. The primary end point was the complete response (CR) rate of high‐risk disease, defined as the absence of high‐risk or progressive disease. Patients were evaluated with cystoscopy and urine cytology every 3 months for the first 2 years, and then every 6 months thereafter for up to 5 years. Directed biopsies were done in the case of abnormal findings on cystoscopy, and random biopsies were done for abnormal cytology findings. The median duration of treatment was 4.2 months (interquartile range, 3.4–9.1 months), with a median of seven administrations. Thirty‐nine of the 96 patients (41%) had a CR in 3 months. The median duration of CR was 16.2 months (95% CI, 6.7–36.2 months). Eighteen (46%) of the 39 patients who had a CR at 3 months had consistent CR at 12 months (19% overall). Overall, 40 patients who initially responded to treatment underwent RC after treatment discontinuation, of whom only three had MIBC (one with pT2N0, one with pT2N1, and one with pT3N1). Thirteen of the 101 patients (13%) experienced grade 3/4 adverse events, of which the most common were hyponatremia and arthralgia. There were no deaths attributed to pembrolizumab treatment.

KEYNOTE‐057 trial cohort B: BCG‐unresponsive papillary tumors alone

Cohort B of the KEYNOTE‐057 trial included 132 patients with BCG‐unresponsive Ta/T1 papillary tumors in high‐risk NMIBC who were enrolled between April 2016 and June 2021. The patients received intravenous pembrolizumab 200 mg every 3 weeks up to 2 years. The patients underwent cystoscopy and urine cytology every 12 weeks for the first 2 years, and every then 24 weeks thereafter until 5 years. Directed biopsies were done for suspicious cystoscopic findings, and random biopsies (including prostatic urethra in men) were done for suspicious high‐grade cytology. The primary end point was high‐risk NMIBC (or worse) disease‐free survival (DFS) at 12 months. The secondary end point was DFS of any disease at 12 months. The 12‐month DFS of high‐risk NMIBC was 43.5% (95% CI, 34.9%–51.9%), with a median DFS of 7.7 months (95% CI, 5.5–13.6 months). The 12‐month DFS of any disease was 41.7% (95% CI, 33.1%–50%), with a median DFS of 6 months (95% CI, 4.3–12 months). Thirty‐six patients underwent RC after pembrolizumab discontinuation; of them, one patient had T2N0 disease and three patients had T3 disease, among whom one had positive nodes (N2). Two patients progressed to metastatic disease. Grade 3/4 adverse events were observed in 19 patients (14%), the most common being colitis and diarrhea. Twenty‐seven patients died, none from treatment‐related adverse events. The study results show that pembrolizumab may be a suitable treatment option for selected patients with BCG‐unresponsive high‐risk NMIBC who are ineligible or unwilling to undergo RC. The 12‐month recurrence‐free survival (RFS) rate threshold of 30%, which was set by the International Bladder Cancer Group, was achieved in this cohort. ¹⁶

SWOG S1605: BCG‐unresponsive high‐risk NMIBC

The SWOG S1605 trial was a single‐arm, phase 2 study evaluating atezolizumab in patients with BCG‐unresponsive high‐risk NMIBC who were ineligible or unwilling to undergo RC. Patients received intravenous atezolizumab 1200 mg every 3 weeks for up to 17 cycles. Patients were monitored with cystoscopy and cytology every 3 months for 24 months, and then every 6 months for the following 36 months. All patients with CIS at study entry underwent a mandatory biopsy at 6 months. The primary study end points were a pathological CR rate at 6 months in patients with CIS (with or without Ta/T1) and event‐free survival (EFS) at 18 months in all available patients. One hundred and twenty‐nine patients were eligible for efficacy analysis: 74 patients with CIS (with or without Ta/T1) and 55 with Ta/T1 tumors. The trial was closed for accrual earlier than expected because of futility; however, the target sample size was achieved. A pathological CR was achieved in 20 (27%) of the 74 patients with CIS, with a median duration of response of 17 months. The 18‐month EFS rate for the 55 patients with Ta/T1 tumors was 49%. Among the 129 eligible patients, seven underwent RC (six of whom had MIBC on pathology) and five patients developed metastatic disease (M1) without preceding evidence of localized MIBC. Grade 3/4 treatment‐related adverse events were observed in 23 (18%) of the 129 patients, and an additional three patients died from treatment‐related adverse events. Although the results of this trial were similar to those reported in other single‐arm trials in this patient population, they did not meet the prespecified thresholds, and the study was considered negative. ¹⁷

THOR‐2 cohort 1: erdafitinib in BCG‐treated high‐risk NMIBC

The THOR‐2 trial was a phase 2, randomized, multicohort study of erdafitinib, a selective pan‐FGFR (fibroblast growth factor receptor) tyrosine kinase inhibitor, in patients with BCG‐treated, high‐risk NMIBC (high‐grade T1/Ta) who had FGFR alterations and declined or were ineligible for RC. Patients were randomized 2:1 to either daily oral erdafitinib (6 mg for up to 2 years) or intravesical chemotherapy (mitomycin C or gemcitabine, with at least four induction doses followed by monthly maintenance for 6 months). The study stopped early because of slow recruitment but randomized 73 patients (49, erdafitinib; 24, chemotherapy). The primary end point (RFS) showed a median RFS of 11.6 months for chemotherapy (95% CI, 6.4–20.1 months), whereas the median RFS for erdafitinib was not reached (95% CI, 16.9 months to not estimable). The hazard ratio (HR) was 0.28 (95% CI, 0.1–0.6; nominal p = .0008), which favored erdafitinib. Safety results were consistent with previously known profiles for both treatments. ¹⁸

Ongoing trials of systemic therapy for NMIBC (Table 2)

KEYNOTE‐676: Efficacy and safety of pembrolizumab in combination with BCG in high‐risk NMIBC (NCT03711032)

The KEYNOTE‐676 trial is a phase 3, randomized controlled study evaluating the efficacy and safety of pembrolizumab in combination with BCG for patients with high‐risk NMIBC. This includes patients whose disease is either persistent or recurrent after BCG induction or who are BCG naive. The trial aims to enroll 1405 participants, and is divided into two main cohorts. Cohort A involves patients who have already received an adequate course of BCG induction for high‐risk NMIBC but who have experienced persistent or recurrent disease. Cohort B consists of patients who have not previously been treated with BCG. ¹⁹

Cohort A has two arms. A1: participants receive BCG (induction and maintenance) combined with pembrolizumab 200 mg administered intravenously every 3 weeks for up to 35 doses (∼2 years). A2: participants receive BCG (induction and maintenance) as monotherapy.

Cohort B includes three arms. B1: participants receive BCG (induction and reduced maintenance) combined with pembrolizumab 400 mg administered intravenously every 6 weeks for up to 9 doses (∼1 year). B2: participants receive BCG (induction and full maintenance) combined with pembrolizumab 400 mg administered intravenously every 6 weeks for up to 9 doses (∼1 year). B3: participants receive BCG monotherapy (induction and maintenance).

The primary outcome for cohort A is the CR rate, defined as the percentage of patients with CIS who achieve a CR in up to 3.5 years. For cohort B, the primary outcome is EFS, defined as the time from randomization to a urothelial carcinoma–related event or death from any cause in up to 5 years. The study is expected to be completed by October 2028.

NCT04164082: Testing the addition of pembrolizumab to intravesical gemcitabine for the treatment of BCG‐unresponsive NMIBC

The clinical trial NCT04164082 is a phase 2 study investigating the combination of intravesical gemcitabine and intravenous pembrolizumab for patients with BCG‐unresponsive NMIBC who are either ineligible for or have declined RC. The trial aims to enroll 161 patients into a single experimental cohort.

Participants receive induction therapy, which consists of pembrolizumab administered intravenously on the first day of cycles 1–4, along with intravesical gemcitabine on days 1, 8, and 15 of cycles 1 and 2. This treatment regimen is repeated every 3 weeks for four cycles, provided there is no disease progression or unacceptable toxicity.

After the induction phase, participants proceed to maintenance therapy, which includes both pembrolizumab and intravesical gemcitabine administered on the first day of each cycle. Maintenance therapy is repeated every 3 weeks for up to 12 cycles, again contingent on the absence of disease progression or unacceptable toxicity.

The primary outcomes of the study include the CR rate at 6 months for patients with a CIS component and EFS at 18 months for the entire study population.

ALBAN (NCT03799835): Atezolizumab plus 1‐year BCG bladder instillation in BCG‐naive high‐risk NMIBC

The ALBAN trial is a phase 3, randomized controlled study designed to evaluate the efficacy of adding atezolizumab to 1 year of intravesical BCG therapy in BCG‐naive patients with high‐risk NMIBC. The trial enrolled 516 patients across 45 centers in Europe, and is now closed for recruitment.

The study has two arms. Arm A (control): patients receive standard BCG therapy, which consists of an induction phase followed by maintenance therapy administered once per week for 3 weeks at weeks 13, 26, and 52 from the start of induction.

Arm B: patients receive the same BCG induction and maintenance schedule in combination with intravenous atezolizumab administered every 3 weeks for up to 1 year, with a maximum of 18 cycles.

The primary outcome of the study is RFS over 2 years, defined as the time to recurrence of any disease (localized or metastatic) after treatment initiation.

PREVERT (NCT03950362): Bladder preservation by radiotherapy and immunotherapy in BCG‐unresponsive NMIBC

The PREVERT trial is a single‐arm, phase 2 study designed to assess the efficacy of avelumab (a PD‐L1 inhibitor) in combination with whole‐bladder radiotherapy for patients with BCG‐unresponsive high‐risk NMIBC. The trial aimed to enroll 67 patients. Participants received radiotherapy, which delivered 60–66 Gy in 30–33 fractions to the entire bladder, with concomitant avelumab. The first cycle of avelumab was administered 5 days before the start of radiotherapy, followed by additional doses every 3 weeks for a total of eight cycles. The primary end point of the study is high‐risk RFS at 1 year.

POTOMAC (NCT03528694): Assessment of the efficacy and safety of durvalumab and BCG compared to standard BCG therapy in NMIBC

The POTOMAC trial is a phase 3, randomized, multicenter study comparing BCG in combination with durvalumab to BCG monotherapy in BCG‐naive patients with high‐risk NMIBC. The trial enrolled 1018 patients globally, and is now closed for recruitment. The study consists of a control arm and two experimental arms, with participants randomized in a 1:1:1 ratio. In the control arm, patients receive standard‐of‐care BCG (induction and maintenance). In one experimental arm, patients receive intravesical BCG (induction and maintenance) along with intravenous durvalumab. In the second experimental arm, patients receive intravesical BCG induction only, in combination with intravenous durvalumab. The primary end point of the study is DFS, with a follow‐up period of up to 4 years. Preliminary results showed a DFS benefit for the combination of durvalumab with BCG (induction and maintenance) versus BCG (induction and maintenance) alone.

ADAPT Bladder (NCT03317158): Modern immunotherapy in BCG‐unresponsive, BCG‐relapsing, and high‐risk BCG‐naive NMIBC

The ADAPT Bladder trial is a phase 1/2 study investigating the safety and efficacy of durvalumab in combination with BCG and radiotherapy in patients with high‐risk NMIBC who are BCG unresponsive, BCG relapsing, or BCG naive. The trial aims to enroll 55 participants across several US centers. In phase 1, the trial will assess the safety of four experimental arms, including durvalumab monotherapy, durvalumab combined with BCG, durvalumab combined with external beam radiotherapy, and durvalumab combined with intravesical gemcitabine/docetaxel. Phase 2 will evaluate the CR rate in patients treated within each of the four arms. CR is defined as the absence of persistent or recurrent high‐grade NMIBC at any posttreatment disease assessment.

CREST (NCT04165317): Sasanlimab in combination with BCG for patients with BCG‐naive high‐risk NMIBC

The CREST trial is a phase 3, randomized, multicenter, multinational, open‐label study evaluating the efficacy of sasanlimab, a PD‐1 inhibitor administered subcutaneously, in combination with BCG in patients with BCG‐naive high‐risk NMIBC. The trial aimed to enroll 1000 patients across Asia, Australia, Europe, and North America, including those with T1 and Ta high‐grade tumors, with or without CIS. All patients must have undergone a complete resection of papillary disease via transurethral resection of the bladder tumor within 12 weeks before randomization. Key exclusion criteria included prior intravesical BCG treatment within 2 years, previous use of anti–PD‐1/PD‐L1/2/cytotoxic T‐lymphocyte‐associated protein 4 agents, or other immunostimulatory therapies; however, prior intravesical chemotherapy was allowed. Participants were randomized in a 1:1:1 ratio into three study arms: A: sasanlimab plus BCG (induction and maintenance); B: sasanlimab plus BCG (induction only); and C: BCG alone (induction and maintenance). The primary end point of the trial was 5‐year EFS. ²⁰ A recent report presented 3‐year landmark EFS outcomes comparing arms A and C. Among patients with CIS, with or without concomitant papillary tumors, the 3‐year EFS rate was 83.0% in arm A and 71.8% in arm C (HR, 0.53; 95% CI, 0.28–0.98). Similarly, in patients with T1 tumors, with or without CIS, the 3‐year EFS rate was 81.3% in arm A versus 72.2% in arm C (HR, 0.63; 95% CI, 0.4–0.96). These findings highlight the potential benefit of combining sasanlimab with BCG in BCG‐naive patients with high‐risk NMIBC. ²¹

DISCUSSION AND FUTURE DIRECTIONS

The treatment landscape for NMIBC, particularly BCG‐unresponsive disease, remains a significant challenge in bladder urothelial carcinoma. Although BCG therapy has long been established as the gold standard for high‐risk NMIBC, a subset of patients inevitably develops resistance or recurrence after adequate BCG treatment. BCG‐unresponsive NMIBC has a high potential for disease progression to MIBC, which carries a much higher mortality risk. In this setting, RC has traditionally been the recommended standard of care; however, the morbidity and impact on quality of life associated with RC make it an infeasible or undesirable option for some patients, which underscores the need for alternative, effective therapeutic strategies. ²² Systemic therapies are being investigated in this setting and may offer a chance for improving outcomes but challenges remain.

Recent advances in systemic therapies, particularly systemic immune checkpoint inhibitors, have opened new options for addressing BCG‐unresponsive NMIBC. Results of the pivotal KEYNOTE‐057 trial, both cohorts A and B, highlight the potential of immunotherapeutic agents such as pembrolizumab as bladder‐sparing alternatives for patients who are ineligible or unwilling to undergo RC. This trial had modest efficacy in terms of CR rates and RFS in selected patients, and outcomes remain suboptimal. In KEYNOTE‐057 cohort A, pembrolizumab achieved a 41% CR rate at 3 months, with a median CR duration of 16.2 months. However, it is important to note that only 19% of the patients maintained a CR at 12 months, which highlights the need for continued improvement in both response rates and durability of response. ¹⁵ The SWOG S1605 trial showed similar outcomes, with a 27% CR rate at 6 months for patients with CIS (with or without Ta/T1) and 49% EFS at 18 months for patients with Ta/T1 tumors. However, this trial did not meet the prespecified thresholds, and was considered negative. ¹⁷

Immunotherapy’s role in NMIBC has primarily focused on agents targeting the PD‐1/PD‐L1 pathway, which has shown promise in solid tumors, including advanced urothelial carcinoma. By inhibiting the PD‐1/PD‐L1 interaction, these therapies enhance the immune system’s ability to recognize and destroy tumor cells that have otherwise evaded immune detection. ²³ , ²⁴ Despite the promising results, these agents are not without limitations. Response rates in clinical trials are relatively low. ²⁵ In KEYNOTE‐057 cohort A, 40 of 96 patients who initially responded to pembrolizumab underwent RC, and three had MIBC. In KEYNOTE‐057 cohort B, 36 of 132 patients who initially responded to pembrolizumab underwent RC; among them, four had MIBC and two developed metastatic disease. In the SWOG S1605 trial, seven of 129 underwent RC; six had MIBC, and five patients developed metastatic disease without preceding evidence of localized MIBC. Furthermore, adverse events remain a concern, with up to 13%–14% of patients in the KEYNOTE‐057 trial and 18% in the SWOG trial experiencing grade 3 or higher treatment‐related toxicities (Figure 1). No deaths were related to adverse events in the KEYNOTE‐057 trial, compared to three patients who died from treatment‐related adverse events in the SWOG S1605 trial. The acceptability of serious therapy‐related toxicity in NMIBC is much lower than with advanced/metastatic urothelial cancer.

FIGURE 1.

Incidence and type of toxicities with systemic immune therapy.

Although systemic immunotherapies represent an important step forward, there is a pressing need for further drug development to address NMIBC. The ongoing efforts to evaluate combination therapies, such as the addition of pembrolizumab to BCG in the KEYNOTE‐676 trial, the use of durvalumab together with BCG in the POTOMAC trial, and the use of pembrolizumab together with intravesical gemcitabine in the NCT04164082 trial, aim to enhance the efficacy of immunotherapy while maintaining a relatively favorable safety profile. These trials underscore the importance of an integrated approach that combines systemic and intravesical therapies. Additional strategies include the use of radiotherapy in combination with immune checkpoint inhibitors, as in the PREVERT and ADAPT Bladder trials. These approaches seek to exploit the potential synergistic effects of radiation‐induced immune activation with checkpoint inhibition, which could potentially overcome resistance mechanisms and improve long‐term outcomes.

In conclusion, although systemic therapy has emerged as an additional treatment option for patients with NMIBC, outcomes are still modest, and there remains a substantial unmet need for new systemic therapeutic agents that can improve outcomes in this challenging population. Ongoing and future trials will be critical in determining the most effective combinations of systemic and intravesical therapies, as well as optimizing patient selection for these emerging treatments. We are optimistic that novel systemic therapies in general, and specifically immunotherapies, will become an increasingly important component in the treatment of early‐stage bladder cancer.

AUTHOR CONTRIBUTIONS

Alon Lazarovich: Writing—original draft; investigation; formal analysis; data curation; writing—review and editing; methodology. Randy F. Sweis: Conceptualization; writing—review and editing; methodology; data curation; formal analysis; supervision; writing—original draft.

CONFLICT OF INTEREST STATEMENT

Randy F. Sweis reports consulting fees from Eisai; research support (to the institution) from ALX Oncology, Ascendis, Astellas, AstraZeneca, Bayer, Bristol‐Myers Squibb, CytomX, Eisai, Genentech/Roche, Gilead, Immunocore, Jounce, Lilly, Loxo, Merck, Mirati, Moderna, Novartis, Pfizer, Pionyr, Pyxis, QED Therapeutics, and Scholar Rock; and the following patent: neoantigens in cancer, PCT/US2020/031357. The other author declares no conflicts of interest.

Lazarovich A, Sweis RF. The current and future role of systemic therapy in non–muscle‐invasive bladder cancer. Cancer. 2025;e35966. doi: 10.1002/cncr.35966