Sequencing, selection, and sparing the bladder in NMIBC

A recent Urology Times Clinical Forum moderated by Gregory C. McMahon, DO, of MidLantic Urology in Pennsylvania, convened practicing urologists to discuss the evolving treatment landscape for BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC). The discussion covered guideline updates, approved and emerging therapies, real-world treatment selection, and the operational demands facing community urology practices managing this complex patient population.

McMahon opened with a review of National Comprehensive Cancer Network and American Urological Association guideline definitions, noting that a recent guideline update expanded the treatment landscape considerably. For patients with BCG-unresponsive NMIBC with carcinoma in situ (CIS), with or without papillary disease, preferred options remain radical cystectomy or clinical trial enrollment, with category 2A recommendations now covering the gemcitabine intravesical system (Inlexzo), intravesical gemcitabine plus docetaxel (Gem/Doce), nadofaragene firadenovec (Adstiladrin), and nogapendekin alfa inbakicept (NAI, Anktiva). Pembrolizumab (Keytruda), available in intravenous and subcutaneous formulations, carries a category 2B designation in this setting. Notably, the update also extended category 2A recommendations to patients with BCG-unresponsive NMIBC with papillary disease only—a change that participants observed will meaningfully expand the eligible treatment population beyond the CIS-focused cohort that has historically defined clinical trial enrollment.

Identifying patients with BCG-unresponsive disease

A significant portion of the discussion addressed the complexity of identifying patients who meet the formal definition of BCG-unresponsive disease. Adequate BCG exposure—often described as a "5-plus-2" framework, comprising at least 5 of 6 induction instillations followed by at least 2 maintenance or reinduction instillations—is a prerequisite for the BCG-unresponsive designation in most circumstances. The sole exception is high-grade T1 disease at the first 3-month evaluation, which qualifies as BCG-unresponsive regardless of prior exposure. Participants acknowledged that clinical practice rarely adheres to the clean lines of trial eligibility criteria: patients with partial responses, those with CIS involving a substantial proportion of the bladder surface, and those who received BCG before the era of these therapies present scenarios that remain clinically unresolved. The group discussed a real-world case of a patient with high-volume CIS who achieved near-complete clearance after nadofaragene yet retained a single biopsy site with persistent disease—a partial response that the trial definition would not have accommodated. The question of whether to re-treat, pivot to a different agent, or refer for cystectomy in such cases was identified as one of the most consequential and least data-supported decisions urologists face.

Quality of transurethral resection of bladder tumor (TURBT) was raised as a foundational issue that directly affects the reliability of staging and, by extension, the validity of therapy selection. Participants debated biopsy technique at the resection base, the frequency of second-look TURBT for high-grade disease, and the variable interpretive practices of pathologists when dealing with cauterized specimens. Several participants indicated they routinely perform second-look resection for high-grade Ta and T1 disease, while acknowledging that this practice is inconsistently applied across community settings. The group also noted that the absence of reliable biomarkers for bladder cancer—in contrast to the well-established role of prostate-specific antigen in prostate cancer management—leaves clinicians dependent on cystoscopy, biopsy results, and pathologic interpretation, all of which carry inherent variability. The CHAI biomarker, an artificial intelligence–based platform that analyzes digitized biopsy slides to predict BCG response, was described as a promising tool with a rapid 48-hour turnaround time. However, its validated comparator remains BCG vs Gem/Doce, requiring extrapolation when applied to other agents. Circulating tumor DNA, available through platforms such as Signatera, was acknowledged as potentially useful for identifying understaged disease but not yet established as a standard monitoring tool in the non–muscle-invasive setting.

Efficacy and safety data for available treatments

McMahon reviewed efficacy and safety data for the 3 intravesical agents with the most evidence in the BCG-unresponsive setting. Nadofaragene, approved by the FDA in 2022, employs a nonreplicating adenoviral vector to deliver the interferon alfa-2b gene into the bladder epithelium, stimulating a local immune response. In its registrational trial, the complete response rate in the CIS cohort was 53%, with a median duration of complete response of approximately 9.7 months; the papillary-only cohort showed a higher response rate of 72% with a median complete response duration of approximately 12 months. Grade 3 adverse events were reported in 4% of patients, with no grade 4 or 5 events observed; the most common adverse effects were catheter-related discharge, bladder spasms, urinary frequency, dysuria, and fatigue. A real-world multisite cohort study reported a complete response rate of approximately 79%, which the group discussed as likely reflecting some degree of understaging in real-world populations rather than genuine therapeutic superiority over trial conditions.

NAI, approved in 2024, is a first-in-class IL-15 superagonist administered intravesically in combination with BCG; it activates natural killer cells, CD8 T cells, and CD4 helper T cells and is intended to induce durable immunologic memory. In the phase 2/3 QUILT-3.032 trial (NCT03022825), the complete response rate at any time was 71%, with rates of 45% and 33% at 12 and 18 months, respectively. Among patients with a complete response at 24 months, the Kaplan-Meier estimated probability of avoiding cystectomy was 89%, and disease-specific survival was 100% in that subgroup. Safety was favorable, with no grade 4 or 5 adverse events and grade 3 events most commonly consisting of hematuria and urinary tract infection—a profile the group characterized as well within the management comfort zone of practicing urologists.

The gemcitabine intravesical system delivers sustained intravesical gemcitabine via a retrievable device over a 21-day cycle. Participants noted that approximately 75% to 80% of the gemcitabine dose is released within the first 2 weeks, that systemic absorption is negligible, and that tissue penetration into deeper layers of the bladder wall has been demonstrated in autopsy models. Tolerability and efficacy were not substantially compromised when the device was retained for at least 14 days rather than the full 21-day period. A cross-trial comparison of pembrolizumab, nadofaragene, and NAI showed complete response rates of 41%, 51% to 59%, and 62% to 71%, respectively, with 12-month complete response durability of 46%, 46%, and 58%.

Sequential intravesical gemcitabine and docetaxel (Gem/Doce), although lacking FDA approval, carries NCCN guideline support and was discussed as a frequently used option, particularly in practices with the operational infrastructure to administer it. The pending phase 3 BRIDGE trial (NCT05538663), a noninferiority study comparing Gem/Doce with BCG, was anticipated as a potentially significant result for the field. Pembrolizumab, a PD-L1 checkpoint inhibitor approved for BCG-unresponsive high-risk NMIBC with CIS in 2020, showed a complete response rate of 41% with a median complete response duration of 16.2 months in the phase 2 KEYNOTE-057 trial (NCT02625961). The subcutaneous formulation was discussed as an operationally practical alternative to intravenous administration. However, participants expressed limited enthusiasm for pembrolizumab monotherapy given its comparatively modest efficacy, systemic adverse effect profile (grade 3 events in approximately 20% of patients across oncology indications), and the expectation that its primary utility will likely be in combination regimens currently under investigation.

Considerations for treatment selection

Treatment selection in practice was discussed frankly. No head-to-head comparative data exist among the approved agents, and no validated biomarker directs clinicians toward one therapy over another beyond the extrapolated CHAI/Vesta signal. Participants described selection as driven by a combination of patient-specific factors (bladder capacity, voiding function, tolerance of prior intravesical therapy, comorbidities), disease characteristics (CIS vs papillary, volume of disease, presence of lymphovascular invasion or variant histology), and operational realities. Nadofaragene's quarterly administration schedule was noted as attractive from a patient convenience standpoint. However, its logistics—including cold-chain requirements and the need for access to infusion centers—have created challenges in some practice settings. NAI’s shelf-stable, reconstitutable powder formulation was described as operationally straightforward. The gemcitabine intravesical system catheter's current single-tip design was identified as a practical limitation for patients with significant prostatic obstruction, with one participant describing difficulty with device placement in such a patient; improvements to catheter options are reportedly in development.

A recurring concern was the financial risk of high-cost therapies. MidLantic Urology's approach of routing all novel bladder-sparing therapy requests through a dedicated Bladder Cancer Committee was described as a mechanism to ensure appropriate patient selection and prompt cystectomy consultation when clinically indicated.

Looking ahead

The forum closed with discussion of the expanding role of immunotherapy and systemic agents in bladder cancer more broadly, including the emerging challenge of counseling patients with muscle-invasive disease who achieve a pathologic complete response to EV-P (enfortumab vedotin-ejfv [Padcev], pembrolizumab) and question the necessity of radical cystectomy—a scenario participants described as increasingly common and without clear data-driven resolution pending results from the phase 3 EV-309 trial (NCT07566156). Participants also acknowledged the volume and multidisciplinary management implications of systemic immunotherapy entering non–muscle-invasive disease: Medical oncologists cannot absorb the volume of patients with high-grade NMIBC, yet most community urology practices have not yet established the referral networks, institutional infrastructure, or comfort level required to manage immune-related adverse events independently. The group expressed optimism that the field's trajectory—mirroring the pattern of progressive treatment intensification seen in metastatic castration-sensitive prostate cancer—will yield improved efficacy as novel agents are introduced earlier in the disease course and combination regimens mature.