What are the management options for advanced urothelial cancer according to European Society for Medical Oncology (ESMO) guidelines?

Advanced Urothelial Cancer Management According to ESMO

For first-line treatment of advanced urothelial carcinoma, enfortumab vedotin plus pembrolizumab is now the preferred regimen, delivering a median overall survival of 31.5 months compared to 16.1 months with platinum-based chemotherapy (HR 0.47). 1

First-Line Treatment Algorithm

Preferred Regimen (All Patients)

• Enfortumab vedotin plus pembrolizumab is the new standard of care, achieving:
  • Overall survival: 31.5 months vs 16.1 months with chemotherapy 1
  • Progression-free survival gain: 6.2 months 1
  • Objective response rate: 67.7% vs 44.4% with chemotherapy 1
  • ESMO-MCBS score: 4 (highest clinical benefit) 1
  • Grade 3+ treatment-related adverse events: 55.9% (lower than chemotherapy at 69.5%) 1

Alternative First-Line Options

For cisplatin-eligible patients who cannot receive enfortumab vedotin:

• Gemcitabine plus cisplatin (GC) remains a strong alternative 1
• High-dose MVAC (methotrexate, vinblastine, adriamycin, cisplatin) with G-CSF 1
• Either regimen should be given for up to 6 cycles 1

For cisplatin-ineligible but carboplatin-eligible patients:

• Carboplatin plus gemcitabine 1
• This combination is inferior to cisplatin-based regimens but appropriate when cisplatin is contraindicated 1

For patients unfit for any platinum-based therapy:

• Single-agent immune checkpoint inhibitors (pembrolizumab or atezolizumab) have a limited role and should not be routinely recommended 1
• These agents may be considered only in highly selected patients with high PD-L1 expression (CPS ≥10 for pembrolizumab, IC ≥5% for atezolizumab) 1

Maintenance Therapy

For patients achieving stable disease or better after platinum-based chemotherapy:

• Avelumab maintenance is mandatory, providing: 1
  • Overall survival gain: 8.8 months 1
  • Median OS: 21.4 months vs 14.3 months with best supportive care 1
  • ESMO-MCBS score: 4 1
• Start avelumab within 4-10 weeks of completing chemotherapy 1
• Continue until disease progression or unacceptable toxicity 1

Second-Line Treatment (After Platinum and Immunotherapy)

The treatment sequence depends on prior therapy:

If Prior Platinum + ICI (Sequential or Concurrent):

1. Enfortumab vedotin (if not used first-line):

   • Overall survival gain: 3.97 months 1
   • HR 0.70 vs chemotherapy 1
   • ESMO-MCBS score: 4 1

2. Erdafitinib for FGFR2/3 alterations:

   • Only for patients with susceptible FGFR3 or FGFR2 genetic alterations 1
   • Overall survival gain: 4.3 months 1
   • HR 0.64 vs chemotherapy 1
   • ESMO-MCBS score: 4 1
   • FDA approved, not EMA approved 1

3. Sacituzumab govitecan:

   • Can be recommended after platinum and ICI 1
   • ESMO-MCBS score: 2 (moderate benefit) 1
   • FDA approved, not EMA approved 1

4. Pembrolizumab (if not previously given):

   • Overall survival gain: 2.9 months 1
   • HR 0.71 vs chemotherapy 1
   • ESMO-MCBS score: 4 1

Critical Management Considerations

Molecular testing requirements:

• FGFR2/3 genetic alterations should be tested in all patients with advanced disease to identify erdafitinib candidates 1
• PD-L1 testing is no longer critical for first-line decisions given the superiority of enfortumab vedotin plus pembrolizumab 1

Cisplatin eligibility criteria (any one criterion makes patient ineligible):

• Creatinine clearance <60 mL/min 1
• ECOG performance status ≥2 1
• Grade ≥2 hearing loss 1
• Grade ≥2 neuropathy 1
• NYHA Class III heart failure 1

Common pitfall: Single-agent immune checkpoint inhibitors should not be used routinely in first-line treatment, even in cisplatin-ineligible patients, as they have demonstrated limited efficacy compared to combination approaches 1. The era of monotherapy immunotherapy in first-line advanced urothelial cancer has effectively ended with the approval of enfortumab vedotin plus pembrolizumab.

Nivolumab plus cisplatin-based chemotherapy showed only modest benefit (OS gain 2.8 months, ESMO-MCBS score: 2) and is not preferred over enfortumab vedotin plus pembrolizumab 1.

Third- and Fourth-Line Options

For patients progressing after enfortumab vedotin plus pembrolizumab, consider treatments not previously given 1:

• Platinum-based chemotherapy (if not used first-line) 1
• Vinflunine or taxanes 1
• Clinical trials with novel agents 1