When BCG Falls Short: What’s Next for NMIBC Patients?

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BCG therapy has served as the cornerstone treatment for high-risk NMIBC since FDA approval in the 1990s. This live, attenuated vaccine is administered directly into the bladder weekly for six weeks, followed by maintenance therapy that can extend up to three years. BCG has demonstrated effectiveness in reducing both recurrence and progression rates to muscle-invasive disease, though it comes with side effects including bladder irritation, urinary discomfort, hematuria and potential infections.

BCG-unresponsive NMIBC is defined as cancer recurrence after adequate BCG therapy, requiring patients to receive at least seven total doses, including induction and maintenance courses. For these patients, traditional guidelines recommend radical cystectomy with urinary diversion as the gold standard treatment. However, this major surgical intervention involves significant risks, including high readmission rates, infection complications and up to 90-day mortality risk in single-digit percentages, making many patients reluctant to pursue this option.

Recent FDA approvals have expanded treatment options for BCG-unresponsive disease beyond radical cystectomy. Approved therapies include pembrolizumab (systemic IV therapy), nadofaragene firadenovec (targeted gene-based adenoviral therapy), and interleukin-15 plus BCG combination therapy. Additionally, intravesical chemotherapy combinations, particularly gemcitabine and docetaxel, are widely utilized based on retrospective studies from the United States and Europe, though not FDA-approved. These developments provide hope for patients facing BCG-unresponsive disease in 2025.