BCG-Unresponsive NMIBC Treatment Selection Requires Balancing Durability, Toxicity, and Patient Priorities

The expanding range of bladder-preserving therapies for BCG-unresponsive high-risk non–muscle-invasive bladder cancer (NMIBC) requires clinicians to look beyond initial complete response (CR) rates when selecting treatment, according to Katie S. Murray, DO, MS, FACS. Response durability, adverse effects, treatment burden, and patients’ reasons for wanting to preserve their bladder should all inform the discussion.¹

During a presentation at the 2026 LUGPA Annual Meeting, Murray reviewed the evidence supporting systemic immunotherapy, intravesical gene therapy, immune stimulation, and sustained intravesical chemotherapy delivery. She emphasized that the available data do not establish a universal sequence for these agents.

“These things will line up differently for every single patient,” Murray said.

Murray is a professor in the Department of Urology at NYU Grossman School of Medicine and chief of urology at NYC Health + Hospitals/Bellevue in New York, New York.

Defining BCG-unresponsive disease and the role of cystectomy

Before choosing a subsequent therapy, clinicians must establish whether a patient meets criteria for BCG-unresponsive disease. Murray outlined persistent or recurrent carcinoma in situ (CIS), with or without papillary disease, within 12 months of adequate BCG; recurrent high-grade Ta or T1 disease within 6 months of adequate BCG; and high-grade T1 disease at the first assessment following induction BCG.¹

She defined adequate BCG exposure as at least 5 of 6 induction doses plus at least 2 of 3 maintenance doses. Establishing the nature and timing of recurrence helps frame both the next treatment decision and eligibility for bladder-preserving approaches.

Murray also emphasized that radical cystectomy should remain part of the discussion. She highlighted guideline recommendations to offer cystectomy to appropriate patients with high-grade T1 disease after induction BCG and to those with persistent or recurrent high-risk disease after additional adequate BCG.

For patients pursuing bladder preservation, understanding the motivation behind that preference is essential. Murray described how concerns about surgery, daily routines, travel, repeated procedures, and treatment-related symptoms may carry different weight for different individuals. A preference to retain the bladder therefore needs to be explored alongside the patient’s expectations for cancer control and willingness to undergo continued treatment and surveillance.

Reviewing approved bladder-preserving therapies

The phase 2 KEYNOTE-057 trial (NCT02625961) evaluated pembrolizumab (Keytruda) in patients with BCG-unresponsive high-risk NMIBC who were ineligible for or declined radical cystectomy. In cohort A, which included patients with CIS with or without papillary tumors, 96 patients were evaluable for efficacy. Pembrolizumab was administered intravenously at 200 mg every 3 weeks for up to 24 months.²

The CR rate was 41% (95% CI, 30.7%-51.1%), and median duration of CR was 16.2 months (95% CI, 6.7-36.2). Among responders, 46% maintained a response for at least 12 months.

Grade 3 or 4 treatment-related adverse effects occurred in 13% of the safety population; serious treatment-related adverse effects occurred in 8%. No treatment-related deaths were reported.

For Murray, route of administration and toxicity are important parts of interpreting these data. Systemic checkpoint inhibition presents a different treatment experience from catheter-based intravesical therapy, making the choice dependent on more than the probability of an initial CR.

Murray also reviewed nadofaragene firadenovec-vncg (Adstiladrin), an intravesical gene therapy designed to promote local production of interferon alfa-2b. Its phase 3 study, CS-003 (NCT02773849), evaluated treatment administered every 3 months.¹˒³

Among 103 efficacy-evaluable patients with CIS with or without papillary disease, 53.4% (95% CI, 43.3%-63.3%) achieved a CR within 3 months. Median duration of CR was 9.69 months (95% CI, 9.17-not estimable). Of the 55 initial responders, 25 maintained a response at 12 months, representing 45.5% of responders and 24.3% of the full CIS efficacy population.

These denominators matter when discussing treatment expectations: the proportion of responders maintaining a response differs from the proportion of all treated patients remaining free of high-grade recurrence.

Murray highlighted the practical features of intravesical delivery, including catheterization, dwell time, storage, and the interval between visits. Although less frequent administration may appeal to some patients, the complete treatment experience remains relevant to shared decision-making.

Another approach, nogapendekin alfa inbakicept-pmln (Anktiva; NAI), is an IL-15 receptor agonist administered intravesically with BCG. Murray reviewed the phase 2/3 QUILT-3.032 trial (NCT03022825), including its published CIS cohort.¹˒⁴

Among 82 patients with CIS with or without papillary tumors, the CR rate was 71% (95% CI, 59.6%-80.3%). Median duration of response (DOR) was 26.6 months (95% CI, 9.9-not reached). Among responders, the estimated probability of maintaining a response was 61.6% at 12 months and 53.2% at 24 months.

The regimen includes weekly induction instillations followed by maintenance treatment. Murray discussed how the need for BCG, repeated catheterization, local urinary symptoms, and the ongoing treatment schedule affect its use in practice.

The FDA expanded the indication for NAI plus BCG on October 14, 2026, to include BCG-unresponsive NMIBC with high-grade papillary tumors without CIS.⁵ The published CIS results Murray reviewed should be distinguished from findings supporting treatment in papillary-only disease.

The gemcitabine intravesical system (Inlexzo; formerly TAR-200) provides sustained local delivery of chemotherapy. Murray reviewed cohort 2 of the phase 2b SunRISe-1 trial (NCT04640623), which evaluated the system as monotherapy in BCG-unresponsive high-risk NMIBC with CIS, with or without papillary disease.¹˒⁶

Among 85 patients, the centrally assessed CR rate was 82.4% (95% CI, 72.6%-89.8%). Median DOR was 25.8 months (95% CI, 8.3-not estimable). Among responders, the estimated 12-month DOR rate was 56.2% (95% CI, 43.4%-67.1%). Grade 3 or higher treatment-related adverse effects occurred in 12.9% of patients, and no treatment-related deaths were reported.

The FDA approved the system in September 2025 for adults with BCG-unresponsive NMIBC with CIS, with or without papillary tumors. Treatment involves insertion every 3 weeks during the first 6 months, followed by every 12 weeks; each system is removed after a 3-week indwelling period.⁷

Murray emphasized that placement, removal, patient tolerance, and office workflow are meaningful considerations when incorporating this delivery approach.

Evaluating additional and investigational approaches

Sequential intravesical gemcitabine and docetaxel remains relevant to bladder-preserving discussions, although the evidence Murray reviewed was retrospective. In a multi-institutional series of 276 patients with recurrent NMIBC following BCG, high-grade recurrence-free survival rates were 65% at 1 year and 52% at 2 years. Only 38% of the cohort met BCG-unresponsive criteria, limiting direct application of the overall results to that population.¹˒⁸

These outcomes should also be distinguished from CR rates reported in CIS-focused prospective trials.

Murray’s overview included the investigational oncolytic immunotherapy cretostimogene grenadenorepvec and the phase 3 BOND-003 study (NCT04452591). She highlighted the CR rate of 75.5% among 110 patients and a 12-month DOR rate of 64.2%.¹ She cautioned against interpreting response rates across separate studies as evidence that one treatment is superior to another.

Aligning treatment with patient priorities and practice logistics

Murray concluded that selecting a bladder-preserving therapy requires weighing efficacy against the realities of receiving and delivering treatment. For patients, those considerations include travel, catheter tolerance, adverse effects, and the frequency and duration of visits. For practices, they include medication handling, staffing, procedure space, scheduling, and support for symptoms between appointments.¹

“How far are they driving to your office?” Murray asked.

Her central message was that the growing number of options makes individualized counseling increasingly important. Treatment selection should account for the durability of cancer control, the burden of therapy, and what each patient hopes to preserve through bladder preservation, while maintaining an ongoing discussion about cystectomy.

References

1. Murray KS. BCG-unresponsive NMIBC: navigating the options. Presented at: LUGPA 2026 Annual Meeting; November 5-7, 2026; Chicago, IL.
2. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22(7):919-930. doi:10.1016/S1470-2045(21)00147-9.
3. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107-117. doi:10.1016/S1470-2045(20)30540-4
4. Chamie K, Chang SS, Kramolowsky E, et al. IL-15 superagonist NAI in BCG-unresponsive non–muscle-invasive bladder cancer. NEJM Evid. 2023;2(1). doi:10.1056/EVIDoa2200167
5. FDA approves expanded indication for nogapendekin alfa inbakicept-pmln for BCG-unresponsive non-muscle invasive bladder cancer. FDA. October 14, 2026. Accessed November 5, 2026.
   https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-expanded-indication-nogapendekin-alfa-inbakicept-pmln-bcg-unresponsive-non-muscle
6. Daneshmand S, van der Heijden MS, Jacob JM, et al. TAR-200 for Bacillus Calmette-Guérin–unresponsive high-risk non–muscle-invasive bladder cancer: results from the phase IIb SunRISe-1 study. J Clin Oncol. 2025;43(33):3578-3588. doi:10.1200/JCO-25-01651.
7. FDA approves gemcitabine intravesical system for non-muscle invasive bladder cancer. FDA. September 9, 2025. Accessed November 5, 2026.
   https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-gemcitabine-intravesical-system-non-muscle-invasive-bladder-cancer
8. Steinberg RL, Thomas LJ, Brooks N, et al. Multi-institution evaluation of sequential gemcitabine and docetaxel as rescue therapy for nonmuscle invasive bladder cancer. J Urol. 2020;203(5):902-909. doi:10.1097/JU.0000000000000688