Pembrolizumab plus BCG elicits high CR rate in BCG-naïve very high-risk T1 NMIBC

The addition of pembrolizumab (Keytruda) to BCG yielded a 92% complete response (CR) rate at 6 months in patients with BCG-naïve “very high risk” T1 non–muscle invasive bladder cancer (NMIBC) who declined upfront radical cystectomy, according to results from a phase 2 trial (NCT03504163).¹

The data were presented at the 2026 American Urological Association Annual Meeting in Washington, DC, by Eugene Pietzak, MD, of Memorial Sloan Kettering Cancer Center.

Pietzak noted that responses appeared to be durable, with a median follow-up of 22 months at the time of data report. However, the regimen also demonstrated a substantial rate (21%) of grade 3 or higher immune-related adverse events.

According to the authors, these findings support pembrolizumab plus BCG as a potential bladder-preserving regimen for patients in this high-risk population who decline cystectomy, though the authors emphasize that these patients must be carefully selected due to the increased toxicity.

Study rationale

Pietzak began by explaining that the trial addresses clinically challenging subgroup of patients with NMIBC who are often considered at particularly high risk for progression with BCG alone but may be unwilling to undergo immediate radical cystectomy.

“High-grade T1 tumors, in particular, are at increased risk for progression, and very high-risk T1 bladder tumors are even more concerning given their risk of clinical understaging and the potential to harbor micrometastatic disease,” Pietzak noted during the presentation. “While definitions of very high risk T1 bladder cancer do vary, nearly all major guidelines recognize this unique clinical entity with an increased risk for progression to BCG alone. Therefore, radical cystectomy is recommended for patients.”

However, Pietzak emphasized the limitations of current management approaches, stating, “Upfront radical cystectomy is overtreatment for the majority of these patients. On the other hand, BCG alone is undertreatment for a substantial proportion as well. Thus, there's a major unmet need for treatment strategy approach that better balances the risks of overtreatment with undertreatment.”

Trial design

The investigator-initiated, single-arm phase 2 trial enrolled 37 patients with BCG-naïve, histologically confirmed high-grade T1 NMIBC with a CIS component and at least 1 additional adverse-risk feature associated with risk of progression. All patients were advised to undergo upfront radical cystectomy but declined surgery.

Eligible patients underwent repeat transurethral resection of bladder tumor (TURBT) and examination under anesthesia within 8 weeks before enrollment. Treatment consisted of pembrolizumab 400 mg intravenously every 6 weeks for up to 9 doses (48 weeks), in combination with induction BCG followed by 12 months of SWOG-style maintenance BCG.

Investigators reported that approximately 70% of enrolled patients had diffuse or multifocal CIS. Common adverse-risk features included T1 tumors larger than 3 cm (68%), extensive lamina propria invasion (57%), and multifocal T1 disease (43%). Nearly two-thirds (73%) of patients had at least 2 adverse-risk features, while more than half (51%) had 3 or more.

The primary end point was 6-month clinical CR. The study used a Simon 2-stage design, with investigators prespecifying that a CR rate of 70% or greater would be considered clinically meaningful in this high-risk population.

Efficacy and safety data

At 6 months, the clinical CR rate was 92% (34 of 37). Investigators stated that responses remained “largely durable” at a median follow-up of 22 months.

“This met our pre-specified threshold to reject the null hypothesis, and we believe that this is a clinically meaningful complete response rate in this very high-risk cohort of patients,” Pietzak noted during the presentation.

During follow-up, 4 patients experienced high-grade recurrence. Two patients underwent radical cystectomy: 1 for recurrent high-grade T1 disease and another after development of a pubovesical fistula in the setting of prior prostatectomy and radiation therapy. Notably, investigators reported no progression events to muscle-invasive or metastatic disease at the time of data cutoff. There was 1 death reported.

The Kaplan-Meier estimated 12-month high-grade recurrence-free survival was approximately 88%, and the estimated 12-month bladder-intact disease-free survival was approximately 94%.

Regarding safety, 33 patients (89%) experienced a treatment-related adverse event (TRAE). The most common TRAEs were fatigue (35%), rash (32%), and pruritus (27%). Grade 3 TRAEs were reported in 32% of patients. Any grade 3 or higher AEs were reported in 43% of patients, and grade 3 or higher immune-related AEs were reported in 21% of patients.

According to Pietzak, these safety data were comparable to other trials of BCG with immune checkpoint blockade in BCG-naïve NMIBC.

Clinical context

Pietzak presented these data against the backdrop of growing interest in treatment intensification strategies for high-risk NMIBC, particularly combinations of intravesical BCG with systemic immune checkpoint inhibition. Over the past year, several major randomized clinical trial readouts, including CREST (NCT04165317), POTOMAC (NCT03528694), and ALBAN (NCT03799835), have evaluated checkpoint inhibitor–based combinations in BCG-naïve high-risk NMIBC populations.

Collectively, these studies have suggested that adding immune checkpoint blockade to BCG may improve CR or recurrence-related outcomes in some patients with high-risk NMIBC. However, the studies also demonstrated increased toxicity associated with systemic immunotherapy, including higher rates of grade 3 or greater AEs compared with BCG alone. Importantly, patients with very high-risk high-grade T1 disease with concomitant CIS represented only a limited proportion of participants in many of these studies, leaving uncertainty regarding the balance of benefit and risk specifically in this subgroup.

“It's also important to put these considerations into perspective with radical cystectomy, which would be recommended for these patients,” Pietzak added during the presentation. “Although the complications with radical cystectomy are different and surgical in nature, it remains a potentially curable option and associated with favorable long-term quality-of-life preservation. So, this needs to be included in informed [decision]-making with these patients.”

However, he noted the promise of this approach for appropriate patients, concluding, “We believe our findings support pembrolizumab plus BCG as a potential bladder-preserving option in carefully selected patients who decline cystectomy, but are at very high risk for progression with BCG alone.”

REFERENCE

1. Pietzak E, Feld E, Frydenlund N, et al. A phase II study of intravenous pembrolizumab combined with intravesical Bacillus Calmette-Guérin (BCG) for patients with BCG-naïve “very high risk” T1 non–muscle invasive bladder cancer traditionally recommended for radical cystectomy NCT03504163. J Urol. 2026;215(5S2). doi:/10.1097/01.JU.0001192572.07890.f8.11