What are the recommended immunotherapy options for patients with bladder cancer, specifically those with advanced or metastatic disease?

Immunotherapy Options for Advanced or Metastatic Bladder Cancer

For patients with advanced or metastatic bladder cancer, immune checkpoint inhibitors are the recommended immunotherapy options, with specific agents selected based on treatment line and patient eligibility for cisplatin-based chemotherapy.

First-Line Immunotherapy Options

For Cisplatin-Ineligible Patients:

1. Standard of Care: Gemcitabine/carboplatin followed by maintenance avelumab in patients whose disease does not progress on chemotherapy 1

   • This approach has the strongest evidence (Level I, A)

2. Alternative Option: Atezolizumab or pembrolizumab monotherapy

   • Only for patients with PD-L1 biomarker-positive tumors
   • Less robust evidence than chemotherapy followed by maintenance avelumab (Level III, B) 1

For Cisplatin-Eligible Patients:

• Cisplatin-based chemotherapy followed by maintenance avelumab in patients whose disease does not progress on chemotherapy (Level I, A) 1

Second-Line Immunotherapy Options

1. Primary Recommendation: Pembrolizumab

   • Most robust evidence for treatment after progression on platinum-based chemotherapy (Level I, A) 1
   • Demonstrated improved overall survival compared to chemotherapy 2

2. Alternative Options:

   • Atezolizumab (Level II, B) 1
   • Nivolumab, durvalumab, and avelumab (Level II, B-III, C) 1

Third-Line and Beyond

For patients who have progressed on both chemotherapy and immunotherapy:

• Enfortumab vedotin (EV) is the recommended standard treatment (Level I, A) 1

Mechanism of Action

Immune checkpoint inhibitors work by blocking the PD-1/PD-L1 pathway:

• Pembrolizumab binds to the PD-1 receptor, blocking its interaction with PD-L1 and PD-L2 3
• This releases PD-1 pathway-mediated inhibition of the immune response against tumor cells 3
• Similar mechanisms apply to other checkpoint inhibitors like atezolizumab, nivolumab, durvalumab, and avelumab 1

Clinical Considerations

Patient Selection:

• PD-L1 testing may help identify patients more likely to respond to anti-PD-L1 therapy, particularly in the first-line setting for cisplatin-ineligible patients 1
• However, durable responses can occur even in patients with low PD-L1 expression 1

Safety Profile:

• Immunotherapy generally has fewer grade 3-5 adverse events compared to chemotherapy 2
• In first-line therapy, immunotherapy reduces grade 3-5 adverse events by approximately 48% compared to chemotherapy 2
• In second-line therapy, immunotherapy reduces grade 3-5 adverse events by approximately 11% compared to chemotherapy 2

Treatment Discontinuation:

• Lower rates of treatment discontinuation due to adverse events with immunotherapy compared to chemotherapy 2
• This is particularly important for elderly patients with bladder cancer who often have multiple comorbidities 4

Common Pitfalls and Caveats

1. First-line immunotherapy limitations:

   • Monotherapy with checkpoint inhibitors in the first-line setting may increase the risk of disease progression compared to chemotherapy (HR 1.33) 2
   • Therefore, chemotherapy followed by maintenance immunotherapy is preferred over immunotherapy alone for first-line treatment 1

2. PD-L1 testing considerations:

   • Different assays are used for different agents (Ventana SP142 for atezolizumab, SP263 for durvalumab) 1
   • PD-L1 is a dynamic biomarker, and archival tumor samples may not reflect current immune status 1

3. Biomarker development:

   • Single biomarker selection (like PD-L1 alone) may be insufficient; integration of multiple biologic components may be required 1
   • MSI-H biomarker positivity may identify patients who could benefit from pembrolizumab regardless of treatment line 1

4. Treatment sequencing:

   • For optimal outcomes, proper sequencing of therapies is crucial
   • The standard approach is platinum-based chemotherapy followed by maintenance immunotherapy in the first-line setting, then second-line immunotherapy upon progression 1

By following these evidence-based recommendations, clinicians can optimize immunotherapy use for patients with advanced or metastatic bladder cancer, potentially improving survival outcomes while maintaining quality of life.