What is the role of PDL1 (Programmed Death-Ligand 1) testing in the diagnostic workup of urothelial carcinoma?

PD-L1 Testing in Urothelial Carcinoma

PD-L1 testing is NOT routinely required for most patients with urothelial carcinoma in 2025, as the preferred first-line treatment (enfortumab vedotin plus pembrolizumab) does not require PD-L1 testing for patient selection. 1, 2

When PD-L1 Testing is NOT Required

The current standard of care for metastatic urothelial carcinoma—enfortumab vedotin plus pembrolizumab—demonstrated superior overall survival (31.5 vs 16.1 months, HR 0.47) without any requirement for PD-L1 testing. 1, 2 This combination is recommended as the preferred first-line option by both the European Association of Urology and European Society for Medical Oncology, with no mention of PD-L1 testing requirements. 2

• For patients receiving enfortumab vedotin plus pembrolizumab, PD-L1 testing provides no clinical utility and should not be performed. 2
• For patients receiving platinum-based chemotherapy followed by maintenance avelumab, PD-L1 testing is also not required. 1
• For second-line treatment with nivolumab, durvalumab, or avelumab after platinum-based chemotherapy, PD-L1 testing is not required. 3

When PD-L1 Testing IS Required

PD-L1 testing is mandatory only in highly specific scenarios where pembrolizumab or atezolizumab monotherapy is being considered as first-line treatment in cisplatin-ineligible patients. 3, 4

Specific Testing Requirements:

• For pembrolizumab monotherapy as first-line treatment: Requires PD-L1 expression with Combined Positive Score (CPS) ≥10 using the 22C3 pharmDx assay. 4
• For atezolizumab monotherapy as first-line treatment: Requires PD-L1 expression on ≥5% of tumor-infiltrating immune cells using the Ventana SP142 assay. 3
• These restrictions apply only to cisplatin-ineligible patients who are not receiving combination therapy with enfortumab vedotin. 3, 4

Clinical Context for PD-L1 Testing

The Society for Immunotherapy of Cancer consensus statement clarifies that while PD-L1 staining using validated assays (SP142 for atezolizumab, SP263 for durvalumab) can identify patients more likely to respond to anti-PD-L1 therapy in the chemotherapy-refractory setting, durable responses occur even in patients with low PD-L1 expression, albeit at lower frequencies. 3

Critical limitation: PD-L1 is a dynamic biomarker, and the relevance of archival tumor tissue to current immune status is unclear. 3

Validated Assays and Their Limitations

Multiple PD-L1 assays exist, but only specific assays have been validated for urothelial carcinoma:

• SP142 (Ventana): Companion diagnostic for atezolizumab, scores tumor-infiltrating immune cells. 3
• SP263 (Ventana): Companion diagnostic for durvalumab, scores tumor-infiltrating immune cells. 3
• 22C3 pharmDx: Companion diagnostic for pembrolizumab, uses Combined Positive Score. 3, 4
• 28-8 pharmDx: Complementary diagnostic for nivolumab. 3

Important caveat: These assays differ in antibodies used, cell types scored (tumor cells vs immune cells), and cutoff values, making them non-interchangeable. 5 Clinicians must follow European Medicines Agency guidance for PD-L1 testing methodology. 3

Predictive vs Prognostic Value

PD-L1 expression predicts objective response rate but NOT overall survival in patients treated with checkpoint inhibitors. 6 A meta-analysis of 2,755 patients demonstrated that PD-L1-positive patients had significantly higher objective response rates (OR 1.82,95% CI 1.18-2.77, p=0.007) but PD-L1 status was not prognostic for 12-month overall survival (OR 0.81,95% CI 0.47-1.40, p=0.45). 6

Interestingly, high PD-L1 expression on tumor-infiltrating immune cells (but not tumor cells) is associated with favorable disease-free and overall survival, representing an independent prognostic predictor. 7

Practical Algorithm for PD-L1 Testing Decisions

1. Is the patient receiving enfortumab vedotin plus pembrolizumab? → NO PD-L1 testing needed. 1, 2

2. Is the patient receiving platinum-based chemotherapy (cisplatin or carboplatin eligible)? → NO PD-L1 testing needed. 1

3. Is the patient cisplatin-ineligible AND being considered for pembrolizumab or atezolizumab monotherapy as first-line treatment? → YES, PD-L1 testing REQUIRED using the appropriate companion diagnostic assay. 3, 4

4. Is the patient being considered for second-line immunotherapy after platinum failure? → NO PD-L1 testing needed for treatment selection, though it may provide enriched information about likelihood of response. 3, 8

Common Pitfalls to Avoid

• Do not use archival tissue without considering temporal changes: PD-L1 expression is dynamic and may change with treatment. 3
• Do not assume assay interchangeability: Different assays use different antibodies, scoring systems, and cutoffs. 5
• Do not withhold immunotherapy based solely on negative PD-L1 status in the second-line setting: Durable responses occur even in PD-L1-low patients. 3
• Do not order PD-L1 testing for patients receiving enfortumab vedotin plus pembrolizumab: This represents unnecessary testing with no clinical utility. 2