What is the recommended treatment protocol for Enfortumab vedotin-ejfv (Antibody-Drug Conjugate) in patients with locally advanced or metastatic urothelial (bladder) cancer?

Enfortumab Vedotin-ejfv Treatment Protocol for Advanced Urothelial Cancer

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

First-Line Treatment Protocol

Dosing and Administration

• Enfortumab vedotin: 1.25 mg/kg intravenously on Days 1 and 8 of a 21-day cycle 1, 2
• Pembrolizumab: 200 mg intravenously on Day 1 of a 21-day cycle (administered approximately 30 minutes after enfortumab vedotin) 2
• Continue treatment until disease progression or unacceptable toxicity 2

Efficacy Data Supporting First-Line Use

• Overall Survival: 31.5 months vs 16.1 months with chemotherapy (HR 0.47; p<0.001) 1, 3
• Progression-Free Survival: 12.5 months vs 6.3 months with chemotherapy (HR 0.45; p<0.001) 1, 3
• Overall Response Rate: 67.7% vs 44.4% with chemotherapy (p<0.001) 1
• Complete Response Rate: 29.1% vs 12.5% with chemotherapy 1

Second-Line or Subsequent Treatment Protocol (Post-Platinum and Immunotherapy)

Dosing and Administration

• Enfortumab vedotin monotherapy: 1.25 mg/kg intravenously on Days 1,8, and 15 of a 28-day cycle 4, 2
• Continue until disease progression or unacceptable toxicity 2

Efficacy Data Supporting Later-Line Use

• Overall Survival: 12.88 months vs 8.97 months with chemotherapy (HR 0.70; p=0.001) 5
• Progression-Free Survival: 5.55 months vs 3.71 months with chemotherapy (HR 0.62; p<0.001) 5
• Objective Response Rate: 44% (95% CI, 35.1%-53.2%), including 12% complete responses 4, 6
• Median Duration of Response: 7.6 months 4, 6

Patient Selection Considerations

Appropriate Candidates

• First-line setting: All patients with previously untreated locally advanced or metastatic urothelial cancer 1
• Later-line setting: Patients who have previously received both:
  • Platinum-containing chemotherapy
  • PD-1 or PD-L1 inhibitor therapy 4, 7

Contraindications and Cautions

• Active CNS metastases
• Ongoing sensory or motor neuropathy Grade ≥2
• Uncontrolled diabetes (HbA1c ≥8% or HbA1c ≥7% with associated diabetes symptoms) 2

Monitoring and Management of Adverse Events

Common Adverse Events

• First-line combination therapy: Grade ≥3 treatment-related adverse events occurred in 55.9% of patients 1, 3
• Later-line monotherapy: Grade ≥3 treatment-related adverse events occurred in 51.4% of patients 5

Specific Adverse Events to Monitor

1. Peripheral neuropathy (50% of patients) 6
2. Skin reactions/rash (48% of patients) 6
3. Fatigue (50% of patients) 6
4. Hyperglycemia (requires monitoring) 7
5. Ocular disorders 7

Dose Modifications

• Real-world data shows that dosing frequency (mean 2.4 treatments per 28-day cycle) and dose (1.1 mg/kg) are often lower than label recommendations in clinical practice 8
• Consider dose reductions for significant adverse events, as 32% of patients in clinical trials required dose reductions 4

Treatment Sequencing Algorithm

1. First-line therapy: Enfortumab vedotin + pembrolizumab (Category 1/highest level recommendation) 4, 1

2. If progression occurs:

   • If FGFR3 or FGFR2 genetic alterations are present: Consider erdafitinib 4
   • If no actionable mutations: Consider alternative chemotherapy options 4

3. If enfortumab vedotin + pembrolizumab is contraindicated:

   • Cisplatin-eligible: Gemcitabine + cisplatin followed by avelumab maintenance 4
   • Cisplatin-ineligible: Gemcitabine + carboplatin followed by avelumab maintenance 4

Clinical Pearls and Pitfalls

• Important: The ESMO-Magnitude of Clinical Benefit Scale score for enfortumab vedotin + pembrolizumab is 4 (on a scale of 1-5), highlighting its significant clinical benefit 4

• Pitfall to avoid: Underdosing is common in real-world practice, with only 58.8% of patients receiving the recommended >2 treatments per 28-day cycle 8. Maintain recommended dosing when possible to optimize outcomes.

• Key consideration: Response rates with enfortumab vedotin are similar across subgroups, including patients with liver metastases and those with no response to prior anti-PD-1/L1 therapy 4, 6