How Can I Keep My Bladder, Doc? The BCG Refractory Non-Muscle Invasive Bladder Cancer Question

Although urothelial carcinoma of the bladder represents the fourth most common malignancy in men, 70% of these cases are non-muscle invasive (NMIBC).  Most of these patients will have outstanding outcomes, however, up to 70% will recur after initial treatment and 10-20% will progress to muscle-invasive bladder cancer (MIBC).1  Once a patient has MIBC, then treatment options become more intense, with discussions of definitive cystectomy, chemotherapy, and radiation, all of which carry greater morbidity and cost. 

The current standard treatment for NMIBC is transurethral resection of bladder tumor (TURBT) with or without intravesicular instillation therapy.  These instillations may include mitomycin C or Bacillus Calmette-Guerin (BCG) depending on the stage and grade of disease.  Although intravesicular BCG is the standard for intermediate and high-risk disease, approximately 50% of patients fail BCG.2  Those patients who have received BCG with disease not permanently eradicated, have a clinical disease state considered to be one of the great unmet needs in urothelial bladder cancer. 

To clarify terminology, BCG-unresponsive disease includes both BCG-refractory and BCG-relapse populations.  BCG-refractory refers to the presence of persistent high-grade cancer 6 months after the start of induction therapy or cancers that have progressed by either stage or grade 3 months after the initiation of induction therapy.3  BCG-relapse refers to patients with recurrence after achieving a ≥6 month disease-free interval after treatment.3  The standard of care for these patients generally remains radical cystectomy.  Intravesicular valrubicin is the only regulatory approved option for BCG-refractory carcinoma in-situ and for those who do not find cystectomy to be a suitable option.  Yet results are generally poor, with a 12-month disease free rate at only 16%.3  As a result, new therapeutics are needed.

Current trials for the BCG-unresponsive disease state have a strong focus on testing many of the newer immune-oncology agents.  This includes moving the PD-1/PD-L1 antibodies already FDA approved for metastatic urothelial carcinoma earlier in the disease course.  For instance, atezolizumab, pembrolizumab, nivolumab, and durvalumab are all being studied either alone or in combination with other agents.  Please see below for more details on some actively accruing trials with PD-1/PD-L1 therapy in the BCG-unresponsive disease state.

Immuno-Oncology Trials for Patients with BCG-Unresponsive Urothelial Cancer

  • Atezolizumab (NCT02844816)
  • Pembrolizumab (Intravesicular) + BCG (NCT02808143)
  • Pembrolizumab – KEYNOTE-057 (NCT02625961)
  • Nivolumab +/- BMS-986205 (IDO-1 inhibitor) +/- BCG (NCT03519256)
  • Durvalumab or Durvalumab + BCG or Durvalumab + radiation (NCT03317158)
  • Durvaluamb and Vicinium (antibody drug conjugate to EPCAM) (NCT03258593)

1. Kaufman DS et al.  Lancet 2009; 374:239-49.
2. Packiam VT et al.  Cancer 2017; 123:390-400.
3. Kamat AM et al.  Nat Rev Urol 2017; 14:244-55.

Written by: Evan Yu, MD