Patient priorities guide treatment choice in BCG-unresponsive NMIBC

Selecting among the growing list of bladder-sparing therapies for BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) requires aligning trial outcomes with each patient’s priorities and each practice’s capacity, according to Katie S. Murray, DO, MS, FACS.¹ Murray, a professor of urology at NYU Langone and chief of urology at Bellevue Hospital in New York, New York, presented “BCG-Unresponsive NMIBC: Navigating the Options” at the 2026 LUGPA Annual Meeting.¹ She declined to offer a fixed treatment sequence, emphasizing individualized decision making instead.¹

Adequate BCG remains essential, Murray said, both for its efficacy and because payers and regulatory labels require patients to meet the BCG-unresponsive definition before receiving newer approved options.¹ She noted the frontline landscape may shift as systemic immunotherapy is added to BCG and as the BRIDGE trial reads out, potentially expanding frontline chemotherapy use.¹

Defining BCG-unresponsive disease and the role of adequate BCG

Six weeks of induction BCG is the consensus standard intravesical therapy for high-risk NMIBC.¹ In a meta-analysis of 6 randomized trials in intermediate- and high-risk disease, 1-year recurrence was 26% with induction BCG vs 51% without BCG.² In a meta-analysis of 24 randomized trials, progression occurred in 260 of 2658 patients (9.8%) receiving BCG vs 304 of 2205 (13.8%) not receiving BCG (P = .001).³

Murray reviewed the FDA definition of BCG-unresponsive disease, noting it was not originally designed as a clinical term but has become one.¹ It includes persistent or recurrent carcinoma in situ (CIS), alone or with recurrent Ta or T1 disease, within 12 months of adequate BCG.¹ It also includes recurrent high-grade Ta/T1 disease within 6 months, or high-grade T1 disease at the first evaluation after induction.¹ Adequate BCG is defined as at least 7 doses: at least 5 of 6 induction doses plus at least 2 of 3 maintenance doses.¹

American Urological Association guideline statement 24 recommends offering radical cystectomy to patients fit for surgery with high-grade T1 disease after a single induction course (moderate recommendation; evidence strength grade C).⁴ Statement 29 recommends offering cystectomy to high-risk patients with persistent or recurrent disease within one year of two induction cycles or BCG maintenance (moderate recommendation; grade C).⁴ Murray said she expects this guidance to remain in place, but noted most patients want to keep their bladders.¹

Aligning patient priorities with complete response, durability, and safety

“You give the people what they want,” Murray said, adding patients often want more than bladder preservation alone.¹ She encourages urologists to help patients identify their priorities, including daily activities and travel, by asking what they would be doing if they were not at the appointment.¹ Common fears include recurrence requiring more transurethral resections, catheters, and treatment adverse events (AEs).

Urologists can then line up each patient’s priorities, fears, loves, and hates with complete response (CR) rates, durability of response, treatment schedule, administration, mechanism of action, and AEs.¹ These factors balance differently for every patient, she said.¹ For a patient whose greatest fear is recurrence, efficacy may outweigh all else, whereas a patient fearful of complications or catheters may prioritize tolerability.¹

Practice sustainability also matters, according to Murray.¹ She advised weighing implementation, storage and handling, patient and personnel time commitments, and the volume of pretreatment and posttreatment phone calls, electronic messages, and emergency department visits.¹

“We have to sustain these open doors so we can continue to treat our patients,” she said.¹

Current guideline options for BCG-unresponsive NMIBC

Under current guidelines shown by Murray, cystectomy and clinical trial enrollment are preferred for BCG-unresponsive CIS with or without papillary disease.¹ Other recommended options include the gemcitabine intravesical system (Inlexzo), intravesical multiagent chemotherapy, nadofaragene firadenovec (Adstiladrin), and nogapendekin alfa inbakicept (Anktiva) plus BCG.¹ Pembrolizumab (Keytruda) and single-agent intravesical chemotherapy (category 2B) are useful in certain circumstances.¹

For papillary-only disease without CIS, the same options are listed, with single-agent intravesical chemotherapy (category 2B) among other recommended options and pembrolizumab listed as category 2B.¹ Murray noted the guidelines had already changed since she submitted her slides.¹ Emerging approaches span 4 mechanistic categories: immune activation, novel intravesical delivery, checkpoint immunotherapy, and chemotherapy.¹

Pembrolizumab and nadofaragene firadenovec: KEYNOTE-057 and CS-003 results

In the phase 2 KEYNOTE-057 trial (NCT02625961), patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles.^5,6 In cohort A (CIS with or without papillary tumors; n = 96 evaluable), the CR rate was 41% (95% CI, 30.7-51.5), with a median CR duration of 16.2 months (95% CI, 6.7-36.2) at a median follow-up of 36.4 months.^5,6 In cohort B (papillary only; n = 132), 12-month disease-free survival (DFS) was 43.5% (95% CI, 34.9-51.9).^5,6

Treatment-related AEs (TRAEs) occurred in 66% of cohort A, with grade 3 or 4 events in 13%, and immune-mediated adverse events occurred in 22%.^5,6 Murray noted pembrolizumab was approved more than 6 years ago and reopened the field of BCG-unresponsive disease.¹ She also distinguished this population from the BCG-naive setting discussed earlier by Tom Jayram, MD, given its prior BCG exposure and different risk profile.¹

The phase 3 CS-003 trial (NCT02773849) evaluated intravesical nadofaragene firadenovec (Adstiladrin), an adenoviral interferon alfa-2b gene therapy given every 3 months, in 157 patients.⁷ At month 3, CR occurred in 55 of 103 patients (53.4%; 95% CI, 43.3-63.3) with CIS, whereas 35 of 48 patients (72.9%) with high-grade Ta/T1 disease remained free of high-grade recurrence.⁶ At month 12, 24.3% of the CIS cohort and 43.8% of the Ta/T1 cohort remained free of high-grade recurrence.⁷

Grade 3 or 4 treatment-emergent AEs occurred in 29 patients (18%), and grade 3 drug-related events in 6 (4%), mainly micturition urgency, bladder spasms, and urinary incontinence.⁷ No grade 4 or 5 TRAEs occurred, and three patients discontinued because of adverse events.^⁶

Nogapendekin alfa inbakicept plus BCG and the gemcitabine intravesical system: QUILT-3.032 and SunRISe-1

The phase 3 QUILT-3.032 trial (NCT03022825) evaluated nogapendekin alfa inbakicept-pmln, an IL-15 superagonist, combined with intravesical BCG in heavily BCG-pretreated patients.^8,9 In cohort A (CIS; n = 82), the CR rate was 71% (95% CI, 59.6-80.3), with a median response duration of 26.6 months and 53.2% of responders maintaining CR at 24 months.⁸ In cohort B (papillary; n = 80), 12-month DFS was 58.2% (95% CI, 46.6-68.2) and 24-month DFS was 52.1%.⁹

Among 180 patients across both cohorts, grade 1 or 2 TRAEs occurred in 109 (61%) and grade 3 TRAEs in 6 (3%), with no grade 4 or 5 events and no grade 3 immune-mediated events.^8,9 Most events were consistent with a localized intravesical profile, including dysuria, pollakiuria, and hematuria.^8,9

In cohort 2 of the phase 2b SunRISe-1 study (NCT04640623), the gemcitabine intravesical system achieved a CR rate of 82.4% (70/85; 95% CI, 72.6-89.8) in patients with CIS.¹⁰ Median time to CR was 2.8 months, and 95.7% of responders achieved CR at the first assessment.¹⁰ Median response duration was 25.8 months, with estimated response durability of 56.2% at 12 months and 51.8% at 24 months.⁹

TRAEs occurred in 71 patients (83.5%), with grade 3 or higher events in 11 (12.9%) and serious TRAEs in 5 (5.9%).¹⁰ The most frequent were pollakiuria (43.5%) and dysuria (40.0%), most resolving after a median of 3.1 weeks, with no treatment-related deaths.⁹ In papillary-only cohort 4, 12-month DFS was 70.2%.¹

Investigational options: Cretostimogene and gemcitabine plus docetaxel

Two investigational approaches are already used regularly in clinical practice, according to Murray.¹ In BOND-003 (NCT04452591), the oncolytic adenovirus cretostimogene grenadenorepvec achieved a CR rate of 75.5% in 110 patients, with 12-month response durability of 64.2% and no grade 3 or higher toxicity.^11,12

Murray noted any discussion of BCG-unresponsive disease is incomplete without sequential intravesical gemcitabine and docetaxel.¹ In a retrospective study of 276 patients with recurrent NMIBC and prior BCG, 2-year high-grade recurrence-free survival among BCG-unresponsive cases was 58% for high-grade papillary disease and 50% for any CIS.¹³ A phase 2 trial, GEMDOCE-BU (NCT07322263), is recruiting patients with BCG-unresponsive high-risk NMIBC.^13,14

Dosing, administration, and practical implementation of BCG-unresponsive NMIBC therapies

Murray cautioned against comparing trials directly, but said dosing and logistics often tip the balance for individual patients.¹ Pembrolizumab requires a 30-minute intravenous infusion every 3 or 6 weeks, with systemic exposure.¹ Nadofaragene firadenovec is instilled every 3 months with a 1-hour dwell, repositioning every 15 minutes.¹

Nogapendekin alfa inbakicept is coadministered with BCG weekly for 6 weeks during induction, with maintenance up to 37 months, a 2-hour dwell, and use within 2 hours of mixing.¹ The gemcitabine intravesical system is inserted by transurethral catheter every 3 weeks during induction, remains indwelling for about 3 weeks, and is removed cystoscopically, then given every 12 weeks during maintenance.¹ Sequential gemcitabine and docetaxel require 2 catheter instillations with dwells of up to 90 and 120 minutes, respectively.¹

The bladder is a storage organ well suited to local therapy with limited systemic effects, Murray noted.¹ Practices must also consider how far patients travel, how much room and staff time each agent requires, and whether administration requires a physician or advanced practice provider or can be delegated to a nurse or medical assistant.¹ These regulations vary by state, so each practice must find where the balance sits for each patient, she said.¹

REFERENCES

1. Murray KS. BCG-unresponsive NMIBC: navigating the options. Presented at: 2026 LUGPA Annual Meeting; November 5-7, 2026, Chicago, Illinois.

2. Shelley MD, Court JB, Kynaston H, Wilt TJ, Fish RG, Mason M. Intravesical bacillus Calmette-Guerin in Ta and T1 bladder cancer. Cochrane Database Syst Rev. 2000;2000(4):CD001986. doi: 101002/14651858.CD001986

3. Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol. 2002;168(5):1964-70. doi:10.1016/S0022-5347(05)64273-5

4. American Urological Association; Society of Urologic Oncology. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline (published 2016; amended 2020, 2024). American Urological Association; 2024. Accessed November 6, 2026. https://www.auanet.org/guidelines-and-quality/guidelines/bladder-cancer-non-muscle-invasive-guideline

5. 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

6. Necchi A, Roumiguié M, Kamat AM, et al. Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2024;25(6):720-730. doi:10.1016/S1470-2045(24)00178-5

7. 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

8. 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):EVIDoa2200167. doi:10.1056/EVIDoa2200167

9. Chang SS, Chamie K, Kramolowsky E, et al. Prolonged progression-free survival, disease-free survival, and cystectomy avoidance with IL-15 receptor lymphocyte-stimulating agent NAI plus bacillus Calmette-Guérin in bacillus Calmette-Guérin-unresponsive papillary-only nonmuscle-invasive bladder cancer. J Urol. 2026;215(1):44-56. doi:10.1097/JU.0000000000004782

10. 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

11. Tyson MD, Smelser WW, Dickstein RJ, Zainfeld DE, Li R. BOND-003-Cohort P: a multi-national, single-arm study of intravesical cretostimogene grenadenorepvec for the treatment of high-risk, papillary only, BCG-unresponsive non-muscle invasive bladder cancer. Urol Oncol. 2025;43(3 Suppl):50-51. doi:10.1016/j.urolonc.2024.12.128

12. Galsky MD, et al. Cystectomy-free survival following cretostimogene grenadenorepovec monotherapy in patients with high-risk BCG-unresponsive non-muscle invasive bladder cancer. J Clin Oncol. 2026;44(suppl 7):abstr 741

13. 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

14. GEMDOCE-BU. ClinicalTrials.gov identifier: NCT07322263. Accessed November 6, 2026. https://clinicaltrials.gov/study/NCT07322263