What is the role of PD1 (Programmed Death-1) testing in patients with advanced urothelial cancer?

PD-L1 Testing in Advanced Urothelial Cancer

Direct Answer

PD-L1 testing is no longer required for most patients with advanced urothelial carcinoma receiving first-line treatment, as enfortumab vedotin plus pembrolizumab is now the preferred regimen and does not require PD-L1 testing for patient selection. 1, 2 PD-L1 testing is only mandatory in the narrow scenario where pembrolizumab or atezolizumab monotherapy is being considered as first-line treatment in cisplatin-ineligible patients. 1

When PD-L1 Testing Should NOT Be Performed

• For patients receiving enfortumab vedotin plus pembrolizumab (the preferred first-line regimen), PD-L1 testing provides no clinical utility and should not be performed. 1 This combination demonstrated superior overall survival (31.5 vs 16.1 months, HR 0.47) regardless of PD-L1 status. 1, 2, 3

• For patients receiving platinum-based chemotherapy followed by maintenance avelumab, PD-L1 testing is not required, as this approach is indicated for all patients achieving stable disease or better after chemotherapy. 2

• In the second-line setting, all approved checkpoint inhibitors can be used without PD-L1 testing requirements. 4, 5

When PD-L1 Testing IS Required

PD-L1 testing is mandatory only when pembrolizumab or atezolizumab monotherapy is being considered as first-line treatment in cisplatin-ineligible patients. 1, 4 This represents a highly specific clinical scenario following FDA and EMA restrictions. 6, 7

For Atezolizumab Monotherapy:

• Requires PD-L1 expression on ≥5% of tumor-infiltrating immune cells using the Ventana SP142 assay. 1
• This is a companion diagnostic requirement for first-line use in cisplatin-ineligible patients. 1, 5

For Pembrolizumab Monotherapy:

• Requires Combined Positive Score (CPS) assessment using the 22C3 pharmDx assay. 1
• This companion diagnostic evaluates tumor cells, lymphocytes, and macrophages. 1, 5

Critical Assay-Specific Requirements

Clinicians must use the specific validated companion diagnostic assay approved for each agent, as different assays are not interchangeable. 4, 1, 5

• Ventana SP142 assay (for atezolizumab): Scores tumor-infiltrating immune cells, requires ≥5% positivity. 1, 5

• 22C3 pharmDx assay (for pembrolizumab): Uses Combined Positive Score methodology, evaluating multiple cell types. 1, 5

• Ventana SP263 assay (for durvalumab): Uses TC ≥25%/IC ≥25% cutoff algorithm. 5, 8

• 28-8 pharmDx assay (for nivolumab): Different scoring methodology from other assays. 5

Important Caveats and Pitfalls

Spatial and Temporal Discordance:

• PD-L1 expression is discordant between primary tumors and metastatic lesions in urothelial carcinoma, with poor agreement (κ = 0.086) in immune cell expression. 9 When feasible, fresh biopsies of metastatic lesions should be used rather than archival primary tumor tissue. 9

• PD-L1 is a dynamic biomarker, and the relevance of archival tumor tissue to current immune status remains unclear. 1

Response Despite Low PD-L1:

• Durable responses to immunotherapy occur even in patients with low PD-L1 expression, albeit at lower frequencies. 4, 1 In the CheckMate 275 trial, objective response rate was 16.1% in PD-L1 <1% patients versus 28.4% in PD-L1 >5% patients. 4

• PD-L1 testing should not be used to withhold second-line immunotherapy, as responses occur across PD-L1 expression levels. 1

Assay Comparability Issues:

• Different PD-L1 assays use different antibodies, platforms, scoring algorithms, and cutoff values, making indirect comparisons challenging. 4, 7, 5 The assay acts as an effect modifier when comparing immunotherapy trials. 4

• Clinicians must follow European Medicines Agency guidance for PD-L1 testing methodology and use only validated assays. 4, 1

Practical Clinical Algorithm

Step 1: Determine if patient is candidate for first-line enfortumab vedotin plus pembrolizumab

• If yes → Do not perform PD-L1 testing 1, 2
• If no → Proceed to Step 2

Step 2: Assess platinum eligibility

• If platinum-eligible → Offer platinum-based chemotherapy followed by maintenance avelumab (no PD-L1 testing needed) 2
• If cisplatin-ineligible → Proceed to Step 3

Step 3: For cisplatin-ineligible patients considering immunotherapy monotherapy

• Perform PD-L1 testing using the appropriate companion diagnostic assay 1
• For atezolizumab: Use Ventana SP142, require ≥5% immune cell positivity 1
• For pembrolizumab: Use 22C3 pharmDx, assess CPS score 1

Step 4: For second-line treatment after platinum failure

• PD-L1 testing is not required for any approved checkpoint inhibitor 4, 5

Prognostic Value (Distinct from Predictive Value)

• High PD-L1 expression on tumor-infiltrating immune cells is associated with favorable disease-free and overall survival, representing an independent prognostic predictor. 1 However, this prognostic information does not directly guide treatment selection in the current treatment paradigm. 1