What is the recommended treatment approach for patients with previously untreated advanced urothelial cancer in the EV-302 (Keynote-A39) trial, using enfortumab vedotin (Adcetris) and pembrolizumab (Keytruda)?

Enfortumab Vedotin Plus Pembrolizumab is the Preferred First-Line Treatment for Previously Untreated Advanced Urothelial Cancer

The combination of enfortumab vedotin plus pembrolizumab is now the standard of care and preferred first-line regimen for patients with previously untreated locally advanced or metastatic urothelial cancer, regardless of cisplatin eligibility, based on the EV-302/Keynote-A39 trial results. 1

Evidence Supporting This Recommendation

The EV-302/Keynote-A39 phase III trial provided compelling evidence for this recommendation:

• Study Design: 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma were randomized to either:

  • Enfortumab vedotin (1.25 mg/kg on Days 1 and 8) + pembrolizumab (200 mg on Day 1) of a 21-day cycle
  • Gemcitabine with either cisplatin or carboplatin 1, 2, 3

• Survival Benefits:

  • Overall Survival (OS): 31.5 months vs 16.1 months (HR 0.47; p<0.001) 1
  • Updated OS with 2.5 years follow-up: 33.8 months vs 15.9 months (HR 0.51) 4
  • Progression-Free Survival (PFS): 12.5 months vs 6.3 months (HR 0.45; p<0.001) 1

• Response Rates:

  • Overall Response Rate (ORR): 67.7% vs 44.4% (p<0.001) 1
  • Complete Response Rate: 29.1% vs 12.5% 1

• Safety Profile:

  • Grade ≥3 treatment-related adverse events: 55.9% with enfortumab vedotin + pembrolizumab vs 69.5% with chemotherapy 1

Implementation in Clinical Practice

The NCCN panel has assigned this combination a Category 1 designation (highest level of evidence and consensus) in both cisplatin-eligible and cisplatin-ineligible settings, making it the only preferred first-line regimen in both scenarios. 1

Dosing Regimen

• Enfortumab vedotin: 1.25 mg/kg IV (maximum 125 mg for patients ≥100 kg) on Days 1 and 8 of each 21-day cycle 3
• Pembrolizumab: 200 mg IV on Day 1 of each 21-day cycle (for up to 35 cycles/2 years) 2
• Treatment continues until disease progression or unacceptable toxicity 2, 3

Patient Selection

This regimen is appropriate for:

• All patients with previously untreated locally advanced or metastatic urothelial cancer
• Both cisplatin-eligible and cisplatin-ineligible patients 1

Important Considerations and Monitoring

Key Adverse Events to Monitor

1. Skin Reactions:

   • Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) can occur
   • Close monitoring is essential, especially during the first cycle 3

2. Peripheral Neuropathy:

   • Occurs in approximately 60.5% of patients receiving the combination 5
   • Monitor for symptoms and manage according to dose modification guidelines 3

3. Hyperglycemia:

   • Regular blood glucose monitoring is recommended 3

4. Pneumonitis/Interstitial Lung Disease:

   • Requires prompt recognition and management 3

Alternative Options

While enfortumab vedotin + pembrolizumab is the preferred regimen, alternative options may be considered in specific circumstances where patients may not be eligible for this combination due to comorbidities:

• Nivolumab + gemcitabine/cisplatin followed by nivolumab maintenance (for cisplatin-eligible patients)
• Cisplatin or carboplatin-containing regimens with avelumab maintenance
• Other chemotherapy regimens or checkpoint inhibitor monotherapy 1

Clinical Perspective

The EV-302 trial results have fundamentally changed the treatment paradigm for advanced urothelial cancer. The NCCN panel noted that these results "entirely change the way that clinicians should be thinking about first-line decision-making" 1. The unprecedented survival benefit (more than doubling median OS compared to chemotherapy) makes this combination the clear first choice for eligible patients.

The European Society for Medical Oncology (ESMO) has also recognized the significance of this treatment, assigning it an ESMO-Magnitude of Clinical Benefit Scale score of 4 (on a scale of 1-5) 1.

Conclusion

The evidence from the EV-302/Keynote-A39 trial demonstrates that enfortumab vedotin plus pembrolizumab provides substantial improvements in survival outcomes with a manageable safety profile compared to standard chemotherapy. This combination represents a major advancement in the treatment of advanced urothelial cancer and should be considered the new standard of care for first-line treatment.