What is the role of immunotherapy, such as pembrolizumab (pembrolizumab) or atezolizumab (atezolizumab), in the treatment of a fit patient with T3N0 urinary bladder cancer?

Role of Immunotherapy in T3N0 Bladder Cancer

Systemic immunotherapy with checkpoint inhibitors (pembrolizumab or atezolizumab) is NOT indicated for localized T3N0 bladder cancer in a fit patient; the standard of care is radical cystectomy with or without neoadjuvant cisplatin-based chemotherapy. 1

Standard Treatment for Localized Muscle-Invasive Disease

For a fit patient with T3N0 bladder cancer, the evidence-based approach is:

• Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the guideline-recommended standard for muscle-invasive bladder cancer (MIBC), including T3 disease 2
• Checkpoint inhibitors remain under active investigation in perioperative settings but are not yet standard of care for localized disease 2
• The current role of immunotherapy in MIBC is limited to clinical trial settings for perioperative use 1

Current FDA-Approved Indications for Checkpoint Inhibitors in Bladder Cancer

Systemic immunotherapy is approved only for metastatic or locally advanced unresectable disease, not for localized T3N0:

Second-Line Metastatic Disease

• Pembrolizumab has Category 1 evidence as preferred second-line therapy after platinum-based chemotherapy, demonstrating superior overall survival (10.3 vs 7.4 months) with fewer grade 3-5 adverse events (15.0% vs 49.4%) 1, 3
• Atezolizumab, nivolumab, durvalumab, and avelumab are FDA-approved for platinum-refractory metastatic disease but with Category 2 evidence 1

First-Line Metastatic Disease (Cisplatin-Ineligible Only)

• Pembrolizumab and atezolizumab are approved as first-line therapy only for patients with locally advanced or metastatic disease who are ineligible for cisplatin-containing chemotherapy 1
• Pembrolizumab achieved 29% overall response rate with 7% complete responses in cisplatin-ineligible patients 1, 4

Investigational Role: Bladder Preservation Protocols

Immunotherapy is being studied in combination with chemoradiation for bladder preservation:

• A phase 1 trial investigating concurrent immune checkpoint inhibition with chemoradiation showed promising metastasis-free and overall survival rates 1
• A phase 3 trial (NCT03775265) investigating atezolizumab with chemoradiation has completed enrollment 1
• One case report described successful bladder preservation using neoadjuvant chemotherapy plus pembrolizumab followed by chemoradiation in a T3b patient, but this remains experimental 5

Critical Pitfalls to Avoid

Do not delay definitive surgical treatment in favor of off-label immunotherapy for localized T3N0 disease:

• T3 disease carries significant risk of progression and requires aggressive local control 1
• Immunotherapy monotherapy has not demonstrated efficacy for localized muscle-invasive disease outside clinical trials 1, 2
• For fit surgical candidates with T3N0 disease, radical cystectomy remains the standard due to high progression risk if undertreated 2

When Immunotherapy IS Appropriate

Consider checkpoint inhibitors only in these specific scenarios:

• Metastatic disease after platinum-based chemotherapy - pembrolizumab preferred 3, 4
• Cisplatin-ineligible patients with metastatic disease - pembrolizumab or atezolizumab 1
• Clinical trial enrollment for perioperative immunotherapy protocols 1, 2
• BCG-unresponsive high-risk non-muscle invasive disease (not applicable to T3) - pembrolizumab 200 mg IV every 3 weeks 2

Biomarker Considerations

• PD-L1 expression identifies patients more likely to respond but is not required for treatment decisions in the metastatic setting, as durable responses occur even with low PD-L1 expression 1
• Pembrolizumab is approved for MSI-H/dMMR solid tumors regardless of site, with 39.6% response rate 1, 4