The optimal management for patients with persistent or recurrent high-grade NMIBC after adequate BCG (e.g., 2 induction 6-week courses or an induction 6-week course and maintenance 3-week course) who are unwilling to undergo or unfit for cystectomy remains to be established. However, this is a rapidly growing space with a number of new agents approved and many more in ongoing trials. Continued investigation through clinical trials of novel therapeutic approaches for such patients remain paramount, and clinicians should seek trials in which to enroll patients. The Panel recognizes that clinical trials may not be available in all such cases, and certain patients may not meet trial eligibility criteria. When clinical trial enrollment is not available for such patients, several options for intravesical immunotherapy/chemotherapy and systemic immunotherapy exist and may be offered.264 To date, no head to head trials of the various agents exist and due to trial design, direct comparisons of efficacy cannot be made. Therefore, at this time, the Panel cannot advocate for one agent over another nor recommend any particular sequencing of agents.  Possible therapies include intravesical valrubicin, administered weekly for six weeks. This regimen is an FDA-approved intravesical treatment for BCG-refractory CIS in patients who are unfit or unwilling to undergo cystectomy. The complete response rate after valrubicin treatment is 18%, and 10% of patients have been found to be disease-free at 1 year following therapy.277 In December 2022, the FDA approved nadofaragene (firadenovec-vncg) for patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors.278 This intravesical medication instilled every 3 months is a suspension of an adenoviral vector-based gene therapy for intravesical instillation. The active ingredient is recombinant, non-replicating adenovirus serotype 5 (Ad5) vector containing a transgene encoding the human IFN-α2b. Phase 3 data reported a 53.4% complete response rate at 3 months after the first dose and 45.5% of the complete responders continued to have a complete response at 12 months.279 In a further follow-up at 5 years, 5.8% of patients with CIS and 15% of patients with high-grade Ta/T1 disease remained free of high-grade recurrence.280 Sequential intravesical gemcitabine and docetaxel have become an alternative for patients with BCG-unresponsive high-grade NMIBC. A retrospective multi-center study published by Taylor et al. in 2025 examined 299 patients with BCG-unresponsive tumors after adequate BCG.281 Patients received either gemcitabine/docetaxel or additional BCG. The study demonstrated improved CSS, progression-free survival, and freedom from cystectomy for patients who received gemcitabine/docetaxel versus BCG alone. Another study examined 12 centers across Europe of patients with BCG-unresponsive bladder cancer and found a 1-year disease-free survival of 79% and progression-free survival of 95%. Although adverse events were common (45%), only 8.7% were Grades 3-4 adverse events.282 It should be noted that this is not a currently FDA-approved treatment. As of January 2020, intravenous pembrolizumab became FDA approved for the treatment of patients with BCG-unresponsive, high-risk NMIBC with CIS with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. The approval is based on findings from the multicenter, open-label, single-arm, multicohort, phase 2 KEYNOTE-057 trial. The study enrolled 148 patients with high-risk NMIBC, 96 of whom had BCG-unresponsive, high-risk NMIBC with CIS. Of those 96 patients, the initial response rate was 41% with 46% of those responders remaining disease-free at 12 months.283, 284 It is important to note that Grades 3-4 adverse events occurred in 13%.284 In 2024, the FDA approved nogapendekin alfa inbakicept-pmln also knows as N-803 based on results from the QUILT trial. N-803 is a mutant interleukin (IL)-15-based immunotherapy fusion protein complex that stimulates natural killer cells and CD8 cells. In cohort A, patients must have had CIS present +/- papillary disease. In the initial trial, the complete response rate was 71% at any time.285 Importantly, N-803 is administered in combination with BCG rather than a single agent. Further updates of this trial examining high-grade papillary disease without CIS have demonstrated a disease-free survival of 58.2% in patients at 12 months and 38.2% at 36 months.285, 286 The latest agent to receive FDA approval for high-grade NMIBC with CIS +/- papillary disease is TAR-200 also known as gemcitabine intravesical drug releasing system (Gem-iDRS). This agent is most notable for its novel delivery system. It is a drug-eluting device that is placed into the bladder and releases gemcitabine. In the SunRISe-1 study, patients with BCG-unresponsive disease demonstrated a 78.8% complete response rate at 3 months and a durability of 45.9% complete response rate at 1 year.287 Additional studies looking at TAR-200 in combination with cetrelimab in patients with papillary disease without CIS and in combination with other agents are ongoing. As mentioned previously, the clinical trial landscape for BCG-unresponsive bladder cancer is very crowded. Other agents that have reported results but have yet to receive FDA approval include EG-70 (detalimogene voraplasmid) in the LEGEND trial, cretostimogene grenadenorepvec (CG0070) in the BOND-003 trial, and cretostimgoene grenadenorepvec and pembrolizumab (CORE-001). A number of these agents have reported promising preliminary results and have already applied for FDA approval. It is notable that most of these agents have been examined in single-arm trials and have variable criteria such as mandatory biopsy in some but not others, allowance of re-induction in some but not others, and different cohorts that allow papillary disease in some but not others. Therefore, at this time, the Panel cannot recommend one agent over another. There is also a lack of data regarding sequencing, and this remains an area for future research.