What are the FDA-approved treatments for BCG (Bacillus Calmette-Guérin) failure in non-muscle-invasive bladder cancer (NMIBC)?

FDA-Approved Treatments for BCG Failure in NMIBC

Pembrolizumab (Keytruda) is currently the only FDA-approved systemic therapy for BCG-unresponsive, high-risk NMIBC with carcinoma in situ (CIS) with or without papillary tumors in patients who are ineligible for or have elected not to undergo cystectomy. 1

FDA-Approved Options

Pembrolizumab (First-Line FDA-Approved Systemic Agent)

• Indicated specifically for BCG-unresponsive, high-risk NMIBC with CIS (with or without papillary tumors) in patients ineligible for or refusing cystectomy 1
• This represents a major advancement as it was the first systemic therapy approved for this indication 2
• Approval was based on the KEYNOTE-057 trial demonstrating clinically meaningful response rates 3

Valrubicin (Only FDA-Approved Intravesical Agent)

• Valrubicin remains the only intravesical drug approved by the FDA specifically for CIS after BCG failure 3
• Approved in 1998, making it the last intravesical agent to receive FDA approval for over two decades 4
• Recognized as an investigator-choice comparator option in clinical trial designs for BCG failure 4

Critical Context: BCG-Unresponsive Definition

BCG-unresponsive disease is defined as either BCG-refractory (persistent high-grade disease at 6 months despite adequate BCG) or BCG-relapsing (recurrence of high-grade disease after achieving disease-free state at 6 months) 5

The FDA accepts single-arm studies for approval in BCG-refractory patients with CIS, requiring clinically meaningful initial complete response rates of at least 50% at 6 months, 30% at 12 months, and 25% at 18 months 4

Standard of Care Recommendation

Radical cystectomy remains the guideline-recommended standard of care for BCG failure, particularly for high-risk patients 4

• Earlier cystectomy (within 2 years of initial BCG treatment) improves 15-year disease-specific survival compared to delayed cystectomy 4
• Cystectomy for recurrent disease shows better survival outcomes than waiting for progression to muscle-invasive disease 4
• For high-grade T1 recurrence after BCG, cystectomy is the recommended treatment (NCCN Category 2A) 4

Alternative Investigator-Choice Options (Not FDA-Approved for This Indication)

While not FDA-approved specifically for BCG failure, the following are recognized as investigator-choice comparators in clinical trials 4:

• Gemcitabine (intravesical)
• Mitomycin C (intravesical)
• Thermochemotherapy

Important caveat: These agents lack FDA approval for BCG-unresponsive NMIBC and should primarily be considered in the context of clinical trials or when FDA-approved options are not feasible 4

Clinical Decision Algorithm

For BCG-unresponsive high-risk NMIBC with CIS:

1. First consideration: Radical cystectomy (gold standard) 4

2. If patient refuses or is ineligible for cystectomy: Pembrolizumab 1, 2

3. Alternative intravesical option: Valrubicin 3

4. If all above are not feasible: Clinical trial participation 5, 6

Common Pitfalls to Avoid

• Do not delay cystectomy until progression to muscle-invasive disease, as this negatively impacts survival 4
• Do not give additional BCG for persistent or recurrent high-grade disease within 6 months of two induction courses or after induction plus maintenance 7
• Do not use reduced-dose BCG as standard therapy, as one-third dose showed inferior disease-free intervals (58.5% vs 61.7% at 5 years, HR 1.15, P=0.045) 8
• Recognize that despite multiple agents under investigation, only valrubicin has achieved FDA approval for intravesical use since 1998, highlighting the difficulty in developing effective therapies for this population 4, 6