What is the recommended use and administration of Enfortumab vedotin (Antibody-Drug Conjugate) for patients with urothelial cancer?

Enfortumab Vedotin for Urothelial Cancer

Enfortumab vedotin combined with pembrolizumab is now the preferred first-line treatment for locally advanced or metastatic urothelial cancer, regardless of cisplatin eligibility or PD-L1 status, based on the landmark EV-302 trial showing a median overall survival of 31.5 months versus 16.1 months with platinum-based chemotherapy. 1

First-Line Treatment Setting

Preferred Regimen

• Enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of a 21-day cycle, combined with pembrolizumab 200 mg on Day 1 of each 21-day cycle 1, 2
• This combination is the only Category 1, preferred first-line regimen for both cisplatin-eligible and cisplatin-ineligible patients 1
• No PD-L1 testing is required for this indication 3
• Continue treatment until disease progression or unacceptable toxicity; pembrolizumab may be continued for up to 2 years 2

Efficacy Data Supporting First-Line Use

• Median progression-free survival: 12.5 months versus 6.3 months with chemotherapy (HR 0.45) 1
• Median overall survival: 31.5 months versus 16.1 months with chemotherapy (HR 0.47) 1
• Objective response rate: 67.7% (29.1% complete response) versus 44.4% (12.5% complete response) with chemotherapy 1, 3

Later-Line Treatment Setting

Indication for Monotherapy

• Enfortumab vedotin 1.25 mg/kg on Days 1,8, and 15 of a 28-day cycle as monotherapy for patients who have received both platinum-containing chemotherapy and a PD-1/PD-L1 inhibitor 1
• This is a preferred subsequent-line systemic therapy option (Category 2A) 1

Efficacy Data for Monotherapy

• Confirmed objective response rate: 44% (12% complete responses) in the EV-201 trial 1, 4
• Median overall survival: 12.88 months versus 8.97 months with chemotherapy (HR 0.70) in the EV-301 trial 1, 5
• Median duration of response: 7.6 months 1
• Similar response rates observed in patients with liver metastases and those with no response to prior checkpoint inhibitor therapy 1, 4

Patient Eligibility Criteria

Exclusions from Treatment

• Active CNS metastases 2
• Ongoing sensory or motor neuropathy Grade ≥2 2
• Uncontrolled diabetes defined as HbA1c ≥8% or HbA1c ≥7% with associated diabetes symptoms 6, 2
• End-stage renal disease with or without dialysis (pharmacokinetics unknown) 2
• Moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST) 2

Acceptable Patient Characteristics

• ECOG performance status 0-2 2
• Age 24-90 years (no dose adjustment needed) 2
• Mild hepatic impairment (no dose adjustment needed) 2
• Renal impairment short of end-stage disease (no dose adjustment needed) 2

Key Toxicities and Management

Most Common Adverse Events

• Rash (48-49%): maculopapular rash is the most common dermatologic toxicity 1, 3, 4
• Peripheral neuropathy (50%): monitor for sensory and motor symptoms 1, 3, 4
• Hyperglycemia: Grade 3 hyperglycemia occurs in 6.1% of patients receiving combination therapy 6
• Ocular disorders: specific monitoring required 3, 6
• Fatigue (50%), alopecia (49%), decreased appetite (44%), dysgeusia (40%) 4

Hyperglycemia Management Algorithm

• Baseline screening: Document HbA1c before treatment initiation 6, 2
• For mild hyperglycemia: Initiate metformin as first-line therapy 6
• For severe hyperglycemia (≥250 mg/dL): Insulin therapy is required 6
• Patients with uncontrolled diabetes (HbA1c ≥8% or HbA1c ≥7% with symptoms) are ineligible for treatment 6, 2

Serious Adverse Events

• Grade ≥3 treatment-related adverse events: 51.4-55.9% with combination therapy 1, 5
• Treatment discontinuation due to adverse events: 12% in monotherapy studies 1
• Dose reductions required in 32% of patients receiving monotherapy 1

Pharmacokinetics and Drug Interactions

Key Pharmacokinetic Parameters

• Peak ADC concentrations occur at end of infusion; peak unconjugated MMAE occurs approximately 2 days after dosing 2
• Elimination half-life: 3.6 days for ADC, 2.6 days for unconjugated MMAE 2
• Minimal accumulation with repeat dosing; steady-state reached after 1 treatment cycle 2

Drug Interactions

• Strong CYP3A4 inhibitors (e.g., ketoconazole): Increase unconjugated MMAE AUC by 38% 2
• Strong CYP3A4 inducers (e.g., rifampin): Decrease unconjugated MMAE AUC by 53% 2
• MMAE is a substrate of P-glycoprotein but not an inhibitor 2
• Unconjugated MMAE is primarily metabolized by CYP3A4 2

Alternative First-Line Options

When Enfortumab Vedotin Is Not Available or Contraindicated

• Gemcitabine plus cisplatin or carboplatin (for cisplatin-eligible patients) 1
• Gemcitabine, cisplatin, and nivolumab: median OS 21.7 months versus 18.9 months with chemotherapy alone (HR 0.78) 1
• Pembrolizumab or atezolizumab monotherapy for cisplatin-ineligible patients with PD-L1 positive tumors (requires PD-L1 testing in this scenario) 3
• Avelumab maintenance therapy following platinum-based chemotherapy: OS gain of 8.8 months (HR 0.76) 1

Real-World Dosing Considerations

Observed Dosing Patterns

• Real-world data shows mean dosing frequency of 2.4 treatments per 28-day cycle (lower than label recommendation of 3 treatments) 7
• Mean dose administered: 1.1 mg/kg (lower than labeled 1.25 mg/kg) 7
• Only 58.8% of patients received an average of >2 treatments per 28-day cycle 7
• These deviations from labeled dosing likely reflect toxicity management in clinical practice 7

Immunogenicity

• Anti-drug antibody formation: 3.6% with monotherapy, 3.0% with combination therapy 2
• Low incidence precludes assessment of impact on pharmacokinetics or efficacy 2