Urothelial Cancer Treatment Guidelines

Introduction

Urothelial cancer treatment guidelines recommend enfortumab vedotin + pembrolizumab as the first-line therapy for patients with previously untreated locally advanced or metastatic urothelial cancer, with a Category 1/highest level recommendation from the National Comprehensive Cancer Network (NCCN) 1, 2

The American Society of Clinical Oncology (ASCO) suggests that enfortumab vedotin + pembrolizumab is the preferred first-line regimen, regardless of cisplatin eligibility, based on the EV-302/Keynote-A39 trial results 1, 2, 3
The NCCN panel has assigned the enfortumab vedotin + pembrolizumab combination a Category 1 designation (highest level of evidence and consensus) in both cisplatin-eligible and cisplatin-ineligible settings 2
The European Society for Medical Oncology (ESMO) has recognized the significance of this treatment, assigning it an ESMO-Magnitude of Clinical Benefit Scale score of 4 (on a scale of 1-5) 4

Enfortumab vedotin monotherapy is administered at 1.25 mg/kg intravenously on Days 1, 8, and 15 of a 28-day cycle, with treatment continued until disease progression or unacceptable toxicity 1
The recommended dosing frequency for enfortumab vedotin is often lower than label recommendations in clinical practice, with a mean of 2.4 treatments per 28-day cycle 1

Enfortumab vedotin + pembrolizumab has an Overall Survival (OS) of 31.5 months vs 16.1 months with chemotherapy, with a Hazard Ratio of 0.47 (p<0.001) 1, 2
The Overall Response Rate (ORR) for enfortumab vedotin + pembrolizumab is 67.7% vs 44.4% with chemotherapy (p<0.001) 1, 2
Complete Response Rate was 29.1% vs 12.5% in favor of the enfortumab vedotin + pembrolizumab combination 2
Progression-Free Survival (PFS) was 12.5 months vs 6.3 months (HR 0.45; p<0.001) in favor of the enfortumab vedotin + pembrolizumab combination 2, 3
Grade ≥3 treatment-related adverse events occurred in 55.9% of patients receiving enfortumab vedotin + pembrolizumab vs 69.5% receiving chemotherapy 2, 3

If progression occurs, consider erdafitinib for patients with FGFR3 or FGFR2 genetic alterations, or alternative chemotherapy options for those without actionable mutations 1, 4
If enfortumab vedotin + pembrolizumab is contraindicated, consider gemcitabine + cisplatin followed by avelumab maintenance for cisplatin-eligible patients, or gemcitabine + carboplatin followed by avelumab maintenance for cisplatin-ineligible patients 1, 4
Alternative options may be considered in specific circumstances where patients may not be eligible for the enfortumab vedotin + pembrolizumab combination due to comorbidities, including nivolumab + gemcitabine/cisplatin followed by nivolumab maintenance, cisplatin or carboplatin-containing regimens with avelumab maintenance, or other chemotherapy regimens or checkpoint inhibitor monotherapy 2

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 1
Dose reductions should be considered for significant adverse events, as 32% of patients in clinical trials required dose reductions 1