There has been a boom in clinical trial activity in patients with bacillus Calmette-Guérin (BCG)-unresponsive high risk nonmuscle invasive bladder cancer (NMIBC) since the AUA/U.S. Food and Drug Administration (FDA) Workshop on this disease state in 2013. This workshop and the ensuing dialogue led to the 2018 FDA Guidance document, which defined this disease state specifically and laid the foundation for clinical trial design.¹ Clear definitions and trial design parameters, as well as a clear pathway to drug registration and a large unmet clinical need, have encouraged many sponsors to test their drugs in these patients who otherwise face radical cystectomy.

The results of single-arm registration trials in patients with BCG-unresponsive carcinoma in situ (CIS) have been reported or published for 5 different agents (summarized in the table), including 2 systemic immunotherapies (pembrolizumab and atezolizumab) and 3 intravesical therapies (nadofaragene firadenovec, oportuzumab monatox, and N-803 plus BCG).^2–6 Pembrolizumab has been approved by the FDA and is now only the second drug after valrubicin to be approved in this disease state. Oportuzumab monatox was declined approval by the FDA in August 2021 pending additional data and analyses, and nadofaragene is currently under review. Parallel to these rigorous trials, we have observed an increased popularity of sequential gemcitabine/docetaxel in North America, which has arguably become the de facto standard of care in these patients based on multicenter retrospective evidence.^7,8

While all these agents are welcome additions to the treatment armamentarium of urologists and medical oncologists, and they represent important options for patients who are truly ineligible for cystectomy or wish to pursue other options over cystectomy, the trial results raise many questions. How do we decide which agent to administer first in patients with BCG-unresponsive NMIBC? What should be the next line therapy if not cystectomy?

Five factors are most likely to guide drug selection in patients with BCG-unresponsive NMIBC:

1. Toxicity: Adverse event profiles, as summarized in the table, favor the use of intravesical agents over systemic immunotherapy. This is likely the most clinically significant difference between intravesical and systemic therapies.
2. Treatment burden: The agents summarized in the table are administered with widely variable schedules. Oportuzumab monatox, for example, is administered 18 times in the first 3 months, during which nadofaragene firadenovec is administered only once. Treatment burden is associated also with additional financial toxicity for the patient.
3. Patient preference: Patients may seek out specific therapies, including systemic immunotherapy, based off perceived benefits. It is important to recognize that some patients may prefer systemic therapy over repeated catherization of the bladder and instillation therapy, and some patients may not be able to hold intravesical drugs long enough to allow these agents to have optimal efficacy.
4. Efficacy: It is challenging to compare outcomes across the various single-arm trials, but these trials were designed with strict inclusion criteria with the intent of being compared to historical controls, so a cross-trial comparison is not unreasonable, although certainly to be viewed with caution. We also need to reserve judgement until we see all study results in peer-reviewed publication and/or after FDA review. Given these significant caveats, N803 plus BCG appears to have better early efficacy than the other agents.
5. Practice patterns: Patients with NMIBC have been managed solely by urologists up until recently. The advent of systemic therapy for NMIBC has brought medical oncologists into this domain, and multidisciplinary care is now important across the bladder cancer spectrum. However, without evidence suggesting that systemic therapy is better than intravesical therapy and in the absence of a contraindication to intravesical therapy, practice patterns will likely determine that intravesical therapy is the default treatment for BCG-unresponsive NMIBC. It is nonetheless essential to inform the patient of all options.
6. Cost: The cost of systemic immunotherapy is established, but the cost of novel intravesical therapies has yet to be determined. A cost comparison is therefore not possible. However, intravesical gemcitabine/docetaxel will cost a small fraction of any novel therapy since both agents are generic. Nonetheless, this needs to be balanced against the absence of clinical trial results for the use of gemcitabine/docetaxel.

Questions about drug sequencing are even more challenging, and there is no compelling evidence to select one agent over another in subsequent lines of therapy. While the trials suggest a low risk of progression of BCG-unresponsive NMIBC in the short term, we know that this risk will increase over time if multiple courses of bladder-preserving medical therapy are used in sequence, and great caution is advised for patients who could pursue cystectomy as the most definitive option. It is also important to recognize that these novel drugs are approved only for CIS with or without papillary disease (Ta/T1), but additional randomized trials will be required before they can be used in patients with BCG-unresponsive Ta/T1 without CIS. Furthermore, trimodal therapy remains an option for patients with T1 bladder tumors.⁹

The treatment of NMIBC continues to evolve rapidly and the future is impossible to predict. Future systemic therapy could include also oral fibroblast growth factor receptor inhibitors (NCT04172675), while novel delivery mechanisms are being developed for the intravesical delivery of immunotherapy in an attempt to avoid systemic toxicity (NCT05120622). Several other novel intravesical agents are under development. Combination therapies (eg NCT03519256) appear to be a logical next step, which may make the debate about systemic vs intravesical therapy moot because we could be combining both (eg NCT04164082). Furthermore, there is a lot of discussion about moving to randomized controlled trials for BCG-unresponsive NMIBC, although that has not been mandated by the FDA.¹⁰

Cover image reprinted from European Urology, Volume 72, Rijnders M, de Wit R, Boormans JL et al: Systematic review of immune checkpoint inhibition in urological cancers. p. 411; 2017: with permission from Elsevier.