High-Risk, Non-Muscle Invasive Bladder Cancer – Is There Anything We Should Be Adding to BCG?

Non-muscle invasive bladder cancer is a topic that I tackled in previous UroToday Clinical Trials Portal articles, including last month’s discussion.  Although transurethral resection is standard of care, recurrence rates are high.  Prognostic factors for recurrence include the number of tumors, tumor size, prior recurrence, stage, grade, and concurrent carcinoma in situ (CIS).1  Patients with high risk features have approximately a 60-70% chance of recurrence and a 10-45% chance of progression to muscle invasive bladder cancer over a 5 year period.  Intravesical Bacillus Calmette-Guerin (BCG) is the standard for intermediate and high-risk disease, but BCG is not adequate to prevent relapses or frank resistance in approximately 50% of treated patients.2

For patients with BCG-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC), radical cystectomy is recommended.  However, many patients are either unfit or choose not to undergo a radical procedure. As a result, many trials have focused on the addition of multiple new immunotherapeutic agents, and I previously summarized those trials back in 2018.1  One of those highlighted trials led to the January 8, 2020, pembrolizumab FDA approval for treatment of BCG-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or who have elected to not undergo radical cystectomy.  This has been a clear unmet medical need, and the addition of pembrolizumab to the treatment options has been welcome. 

An intravesical option that does not carry risk of systemic autoimmune adverse events, and is easy for administration by urologists, would be a welcome new addition.  Just last month, I wrote an article summarizing the state of ongoing, accruing clinical trials for this disease state, with a focus on the next generation of clinical trials beyond pembrolizumab.2

At the 2022 Genitourinary Cancers Symposium, a phase II/III trial of the IL-15RalphaFc superagonist N-803 was presented when combined with BCG for patients already with BCG-unresponsive non-muscle invasive bladder cancer.5  Unlike some other intravesical therapies that are not utilized in combination with BCG, it is felt that training or priming by BCG may be necessary for N-803 to work more effectively.6  This training or priming can lead to an improved innate immune response by N-803 when used together with BCG.  Meanwhile, N-803 serves to drive the proliferation and activation of NK and T cells, without binding to T regulatory cells.  Uniquely, N-803 has an IgG1 Fc that increases lymphatic homing and also the overall half-life.  N-803 effectively serves as the secondary stimulus or boost to the prime provided by BCG.

In regards to the clinical data, N-803 showed complete response in 9 of 9 subjects when combined with BCG in a phase 1 trial.7  The QUILT 3.032 trial, presented data from two separate cohorts at the 2022 Genitourinary Cancers Symposium.  Cohort A patients had persistent or recurrent CIS +/- recurrent Ta/T1 disease within 12 months of receiving adequate BCG, while Cohort B patients had recurrent high-grade Ta/T1 disease within 6 months of completing adequate BCG.  BCG 50 mg plus N-803 400 ug was administered intravesically weekly X6 induction or reinduction X6 plus maintenance for up to 3 years.5  This patient population was heavily BCG pretreated with a median number of doses being 12.  In Cohort A, complete response was noted in 59 of 83 (71%) at the primary endpoint designated 3- or 6-month time point.  Impressively, more than half (52%) had durable response out to 2 years or beyond.  In Cohort B, the papillary tumor group, the primary endpoint of being disease free at 12 months was achieved in 57% of the 77 patients enrolled.  At 2 years, the disease-free survival rate was still 48%.  Adverse events were minimal in grade 1-2, most commonly being dysuria (22%), pollakiuria (19%), and hematuria (18%).  The above results are quite impressive, leaving promise that we may eventually have another option for patients with BCG-unresponsive non-muscle invasive bladder cancer.

Although there is an ongoing issue with a worldwide BCG shortage, studies like QUILT 3.032 beg the question as to whether we ought to be performing more trials with novel agents in combination with BCG.  Perhaps there are more opportunities for additive or even synergistic effect, and this concept of priming or training with BCG should be further studied in the BCG unresponsive non-muscle invasive bladder cancer disease state.  Additionally, with around half the patients with high-risk non-muscle invasive bladder cancer relapsing after BCG, we should be dedicated to studying more up-front combination treatments to potentially decrease the number of our patients that end up with BCG unresponsive non-muscle invasive bladder cancer.

Below, I present ongoing trials that I believe we should aggressively accrue to, with the dedicated focus on combining agents with BCG.  Some of these trials are for patients receiving up-front induction + maintenance, others are for BCG-unresponsive disease states, and some trials are accruing patients with both of these disease states.

Trials for Patients with high-risk BCG Naïve Urothelial Cancer

  • TACBIN – Phase 1/2 trial of Teslelizumab (anti-PD-1 antibody) with BCG (NCT04922047)
  • Phase 1b/IIb of N-803 plus BCG versus BCG (NCT02138734)
  • Adjuvant propranolol plus BCG (NCT04493489)
  • Phase 3 trial of Sasanlimab (Subcutaneously delivered anti-PD-1 antibody) alone or with BCG (NCT04165317)
  • BladderGATE – Phase 1 trial of Atezolizumab and BCG (NCT04134000)
  • ALBAN – Phase 3 trial of Atezolizumab with BCG vs. BCG (NCT03799835)
  • HR NMIBC KEYNOTE-676 – Phase 3 trial of Pembrolizumab and BCG vs. BCG (NCT03711032)
  • FB10 – Intravesical Electromotive Mitomycin-C and BCG (NCT03664869)

Trials for Patients with BCG-Unresponsive Urothelial Cancer

  • ADAPT-BLADDER – durvalumab with radiation and BCG for BCG relapsing patients (NCT03317158)
  • QUILT 3.032 – Phase 2/3 trial of Intravesical BCG plus ALT-803 (IL-15 superagonist) (NCT03022825)
  • Phase 1/2 trial of BCG with gemcitabine (NCT04179162)
  • Phase 3 trial of Sasanlimab (Subcutaneously delivered anti-PD-1 antibody) alone or with BCG (NCT04165317)
Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington


  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. Yu EY. From the desk of Evan Yu: How can I keep my bladder, Doc? The BCG refractory non-muscle invasive bladder cancer question.  Urotoday Clinical Trials Portal.  July 9, 2018.
  4. Yu EY. From the desk of Evan Yu: Pembrolizumab and beyond for BCG-unresponsive, high-risk, non-muscle invasive bladder cancer. Urotoday Clinical Trials Portal.  April 1, 2022.
  5. Chang SS, et al. Positive efficacy and safety phase 3 results in both CIS and papillary cohorts BCG-unresponsive nonmuscle invasive bladder cancer (NMIBC) after IL-15RαFc superagonist N-803 (Anktiva) and BCG infusion. J Clin Oncol 40, no. 6_suppl (February 20, 2022) 431-431.
  6. van Puffelen JH, et al. Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer. Nature Rev Urol 2020; 17:513-25.
  7. Rosser CJ, et al. Safety, Tolerability, and Long-Term Clinical Outcomes of an IL-15 analogue (N-803) Admixed with Bacillus Calmette-Guérin (BCG) for the Treatment of Bladder Cancer. OncoImmunology 2021; 10:e1912885.
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