Is PD-L1 (Programmed Death-Ligand 1) testing required prior to initiating therapy with enfortumab vedotin (EV) and pembrolizumab (pembro) for metastatic urothelial cancer?

PD-L1 Testing is Not Required for EV and Pembrolizumab in Metastatic Urothelial Cancer

PD-L1 testing is not required prior to initiating therapy with enfortumab vedotin (EV) and pembrolizumab (pembro) for metastatic urothelial cancer. The EV-302 trial demonstrated unprecedented efficacy of this combination regardless of PD-L1 status 1.

Evidence Supporting No PD-L1 Testing Requirement

• The EV-302 trial showed that EV plus pembrolizumab demonstrated superior overall survival (OS) of 31.5 months versus 16.1 months with platinum-based chemotherapy (HR 0.47), without patient selection based on PD-L1 status 1
• The European Association of Urology guidelines (2025) recommend EV plus pembrolizumab as the new standard of care for patients eligible for combination therapy, with no mention of PD-L1 testing requirement 1
• The European Society for Medical Oncology (ESMO) clinical practice guidelines also recommend EV plus pembrolizumab without requiring PD-L1 testing 1

Contrast with Previous PD-L1 Testing Requirements

• PD-L1 testing was previously required for certain immunotherapy treatments in specific contexts:
  • Atezolizumab and pembrolizumab as first-line treatments for cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma required PD-L1 expression 1
  • The FDA approved companion diagnostic tests for measuring PD-L1 expression specifically for these earlier indications 1

Clinical Efficacy of EV Plus Pembrolizumab

• The EV-302 trial demonstrated:
  • Objective response rate of 67.7% (29.1% complete response) versus 44.4% (12.5% complete response) with platinum-based chemotherapy 1
  • Median progression-free survival of 12.5 versus 6.3 months (HR 0.45) 1
  • Median overall survival of 31.5 versus 16.1 months (HR 0.47) 1
• In the EV-103 phase Ib/II study (Cohort K), cisplatin-ineligible patients treated with EV plus pembrolizumab showed:
  • Confirmed objective response rate of 64.5% (95% CI, 52.7-75.1) 2
  • Durable responses with 65.4% of responders maintaining response at 12 months 2

Safety Considerations

• Common grade 3 or higher treatment-related adverse events with EV plus pembrolizumab include:
  • Maculopapular rash (17.1%), fatigue (9.2%), and neutropenia (9.2%) 2
  • Skin reactions (67.1%) and peripheral neuropathy (60.5%) are common adverse events of special interest 2
• The key EV toxicities include rash, neuropathy, ocular disorders, and hyperglycemia 1

Clinical Algorithm for Treatment Selection

1. First-line treatment for metastatic urothelial cancer:

   • EV plus pembrolizumab is the preferred first-line option for patients eligible for combination therapy (PS 0-2, GFR >30 ml/min, adequate organ functions) 1
   • No PD-L1 testing is required 1

2. If patient is not eligible for EV or EV is not available:

   • For PD-L1 positive patients: Consider platinum/gemcitabine plus atezolizumab or pembrolizumab 1
   • PD-L1 testing would be required in this scenario 1

3. After progression on EV plus pembrolizumab:

   • Consider platinum-based chemotherapy as second-line therapy 1
   • The role of maintenance avelumab (PD-L1 inhibitor) in this sequence remains unclear 1

Conclusion

The combination of enfortumab vedotin plus pembrolizumab has demonstrated unprecedented efficacy in metastatic urothelial carcinoma, with a median overall survival of 31.5 months 1. Unlike some previous immunotherapy regimens, this combination does not require PD-L1 testing prior to initiation, making it a more accessible treatment option for patients with metastatic urothelial cancer.