2. UroToday Home
  3. Clinical Trials
  4. From the Editor
Back to From the Editor Articles    

Finding Substitutes for Intravesical Bacillus Calmette-Guerin (BCG) for High-Risk, Non-Muscle Invasive Bladder Cancer (NMIBC) – What’s Around the Corner?

Non-muscle invasive bladder cancer (NMIBC) is a pesky topic due to high recurrence rates after transurethral resection. Prognostic factors for recurrence include number of tumors, tumor size, prior recurrence, stage, grade, and concurrent carcinoma in situ (CIS).1 Patients with high-risk features have a 60-70% likelihood of recurrence and a 10-45% rate of progression to muscle-invasive bladder cancer over a 5 year period. Intravesical Bacillus Calmette-Guerin (BCG) is the cornerstone of treatment for intermediate and high-risk disease due to its ability to stimulate an immune response that helps prevent tumor recurrence. However, BCG is not adequate to prevent relapses or frank resistance in approximately 50% of treated patients.2 To make matters more challenging, there has been a persistent worldwide shortage of BCG, coupled with increased global demand over recent years. This shortage has spurred efforts on multiple fronts: regulatory and manufacturing solutions to restore BCG supply and clinical research to identify and validate substitute treatments that can safely and effectively replace BCG therapy.

The BCG shortage is multifactorial. Merck & Co., the sole manufacturer of the TICE® strain used in many regions, faces production challenges due to the lengthy, complex manufacturing process of this live attenuated vaccine. Increased global demand, driven not only by rising bladder cancer incidence but also by off-label uses, has compounded the problem. In addition, sporadic manufacturing issues (such as production facility closures and quality control setbacks) have periodically constrained the available supply. These disruptions have forced clinicians to ration BCG, limit dosing schedules, and even postpone treatment for some patients, potentially increasing the risk of cancer recurrence and progression. Some centers are adopting reduced-dose regimens and modifying induction and maintenance schedules to extend the limited supply. These modified protocols are being guided by emerging data that suggest a reduced dose may trigger an adequate immune response in BCG-vaccinated populations, such as in countries where newborn BCG vaccination is routine.3

To address this critical shortage, several other measures are underway. First, Merck is hoping to triple its current production capacity by building a new manufacturing facility in Durham, North Carolina. However, this expansion could take several years before it fully mitigates supply constraints. Other substitute strategies include the importation of BCG strains from different regions. Some countries produce alternative BCG strains that have shown similar efficacy to the standard TICE® strain used in the United States. However, importing these strains can be costly and time-consuming due to regulatory and logistical hurdles. The recent FDA authorization for an expanded access program (EAP) to provide a recombinant BCG (rBCG) may provide some relief in the interim.4 While phase 1/2 clinical trials have yielded encouraging results regarding safety and immunogenicity with rBCG, the long-term efficacy and durability of rBCG in a broader, more diverse patient population remain to be fully established. Although rBCG is intended to address supply shortages, the recombinant nature of the product may incur higher manufacturing costs. Ensuring a consistent, scalable supply while managing potential cost increases will be essential for the long-term sustainability of this therapeutic option. Finally, the FDA’s expanded access authorization is designed to provide an immediate treatment option, but it is not a substitute for full market approval. As such, the use of rBCG under this program is subject to limitations and may not fully represent its performance in a standard commercial setting.

Parallel to efforts aimed at expanding BCG production, significant research is focusing on substitute treatments that can serve as alternatives during the shortage. One promising approach is the use of combination intravesical chemotherapy. Gemcitabine combined with docetaxel (gem/doce), as first-line therapy in patients with high-risk NMIBC, has achieved recurrence-free survival rates comparable to—or even exceeding—those typically observed with BCG treatment. For instance, one study reported an 82% cancer-free survival rate at two years with gem/doce.5

For BCG unresponsive NMIBC, there are already multiple other agents being used, including pembrolizumab, nadofaragene firadenovec, and nogapendekin alfa inbakicept. The latter, however, requires combination with BCG, and none of these newer agents are regulatory approved for first-line NMIBC use.

At the American Urological Association 2025 meeting, we just saw promising data presented, using TAR-200 for BCG unresponsive NMIBC.6,7 However, one presentation focused on the CREST study, evaluating first-line high-risk NMIBC. This trial introduced systemic sasanlimab (anti-PD-1 antibody) to BCG induction followed by maintenance and found that it had superior outcomes over BCG induction followed by maintenance for high-risk NMIBC.8 The primary endpoint was event free survival (EFS), which included recurrence of high-grade disease, progressive disease, persistence of carcinoma in situ (CIS), or death from any cause. With a median followup for event free survival of 36.3 months, the CREST study showed a 32% lower event free survival (HR 0.68, 0.49-0.94) with combination therapy compared to BCG alone, with a 1-sided p-value of 0.0095. The toxicities were as anticipated for each agent, although there was an 11.4% increase in lipase, 9.4% increase in lipase, 8.6% increase in ALT, and 8.6% increase in AST in the sasanlimab arm; none of these were significantly seen in the BCG only arm.

Although this data is fairly impressive, and it should strongly be considered moving forward if regulatory approval is granted, this is another combination regimen that includes BCG and does not help with the current shortage. Besides the integration of the remedial actions and alternative treatments above, the ideal mitigation strategy for the BCG shortage is continued research into substitute agents that will also broaden the treatment landscape for bladder cancer in the future. Below, I present a dedicated focus on ongoing clinical trials for patients with high-risk NMIBC, using strategies that do not include BCG, rather focusing on novel therapeutic agents.

Trials for Patients with high-risk Non-Muscle Invasive Bladder Cancer that do not include BCG

  • Submucosal injection of Pseudomonas Aeruginosa for intermediate and high risk NMIBC (NCT05975151)
  • Intravesical 9MW2821, a nectin-4 antibody drug conjugate for high-risk NMIBC (NCT06551233)
  • Intravesical disitamab vedotin for patients with high-risk NMIBC that express HER2 (NCT06378242)
  • Hyperthermic Intravesical Chemotherapy (HIVEC) with Gemcitabine for intermediate and high-risk NMIBC (NCT06327932)
  • Intravesical Cretostimogene Grenadenorepvec for high-risk NMIBC (NCT06567743)
  • Intravesical Mitomycin C for high-risk NMIBC (NCT06696794)
  • Disitamab Vedotin combined with Tislelizumab for HER2 overexpressing high-risk NMIBC which is not completely resectable (NCT05495724)
  • ADVANCED-2: Intravesical TARA-002 (Streptococcus pyogenes Type A, Type 3) for high-grade NMIBC (NCT05951179)
  • Intravesical SHR-2005 for intermediate and high-risk NMIBC (NCT06108492)
  • Disitamab Vedotin combined with Tislelizumab and re-TURBT for HER2 high-expressing high-risk and very high-risk NMIBC (NCT06630871)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Tse J, et al. Current advances in BCG-unresponsive non-muscle invasive bladder cancer. Expert Opin Investig Drugs 2019; 28:757-70.
  2. Packiam VT, et al. Non-muscle-invasive bladder cancer: Intravesical treatments beyond Bacille Calmette-Guérin. Cancer 2017; 123:390-400.
  3. Lidagoster S, et al. BCG and Alternative Therapies to BCG Therapy for Non-Muscle-Invasive Bladder Cancer. Curr Oncol 2024; 31:1063-78.
  4. https://www.businesswire.com/news/home/20250219106197/en/FDA-Authorizes-ImmunityBio-to-Provide-Recombinant-BCG-rBCG-to-Urologists-to-Address-TICE%C2%AE-BCG-Shortage
  5. McElree IM, et al. Comparison of Sequential Intravesical Gemcitabine and Docetaxel vs Bacillus Calmette-Guérin for the Treatment of Patients With High-Risk Non–Muscle-Invasive Bladder Cancer. JAMA Netw Open 2023; 6:e230849.
  6. Jacob J, et al. TAR-200 monotherapy in patients with bacillus Calmette-Guerin-unresponsive high-risk non-muscle-invasive bladder cancer carcinoma in situ: 1-year durability and patient-reported outcome. American Urological Association 2025 Annual Meeting. Oral presentation P2s.
  7. Guerrero-Ramos F, et al. TAR-200 monotherapy in patients with bacillus Calmette-Guerin-unresponsive papillary disease- only high-risk non-muscle-invasive bladder cancer: first results from Cohort 4 of SunRISe-1. American Urological Association 2025 Annual Meeting. Oral presentation P2s.
  8. Shore N, et al. Sasanlimab in combination with Bacillus Calmette-Guerin improves event-free survival versus Bacillus Calmette-Guerin as standard of care in high-risk non-muscle-invasive bladder cancer. American Urological Association 2025 Annual Meeting. Oral presentation P2s.