What is the first line management of metastatic (mets) urothelial cancer?

First-Line Management of Metastatic Urothelial Cancer

Enfortumab vedotin plus pembrolizumab is now the preferred first-line treatment for metastatic urothelial carcinoma based on the remarkable survival benefit demonstrated in the EV-302 trial. 1

Current Treatment Algorithm

First-Line Options Based on Patient Eligibility

• Preferred First-Line Treatment: Enfortumab vedotin plus pembrolizumab (EV+P)

  • Demonstrated significant improvement in overall survival (OS) compared to platinum-based chemotherapy (31.5 months vs 16.1 months; HR 0.47) 1
  • Higher objective response rate (67.7% vs 44.4%) with a favorable safety profile compared to chemotherapy 1
  • Grade 3 treatment-related adverse events were lower with EV+P (55.9%) compared to platinum-based chemotherapy (69.5%) 1

• For Patients Ineligible for EV+P:

  • Cisplatin-eligible patients: Cisplatin-based combination chemotherapy (gemcitabine plus cisplatin) 1

    • Historically the standard of care with median OS of approximately 13 months 1
    • Should be followed by maintenance avelumab for patients who achieve stable disease or better 1

  • Cisplatin-ineligible patients: Carboplatin-based chemotherapy (carboplatin plus gemcitabine) 1

    • Should also be followed by maintenance avelumab for non-progressing patients 1

• For PD-L1 positive patients who are ineligible for any platinum-based therapy:

  • Pembrolizumab or atezolizumab monotherapy 1
  • Based on single-arm phase II studies showing objective response rates of 26-39% 1

Management After First-Line Treatment

Maintenance Therapy

• For patients who achieve stable disease or better with platinum-based chemotherapy:
  • Maintenance avelumab significantly improves OS (21.4 vs 14.3 months; HR 0.69) 1
  • Should be started within 10 weeks of completing first-line chemotherapy 1

Second-Line Treatment Options

• After progression on first-line therapy:
  • Pembrolizumab 1
  • Erdafitinib (for FGFR3-altered tumors) 1
  • Enfortumab vedotin (if not used in first line) 1
  • Consider platinum rechallenge in select patients who had good response to initial platinum therapy 2

Special Considerations

• Monitoring and Management of Treatment-Related Toxicities:

  • EV+P requires careful monitoring for skin reactions, peripheral neuropathy, and immune-related adverse events 3
  • Early recognition and management of these toxicities is essential for treatment continuation and optimal outcomes 3

• Treatment Selection Factors:

  • Performance status, renal function, and comorbidities should guide treatment selection 1
  • Approximately 40% of patients are not fit for cisplatin-containing therapy due to poor performance status, impaired renal function, or comorbidities 1

• Biomarker Testing:

  • PD-L1 testing is recommended for patients ineligible for platinum-based therapy 1
  • FGFR3 mutation testing should be considered for potential second-line treatment with erdafitinib 1

• Treatment Sequencing:

  • The optimal treatment sequence continues to evolve with new evidence 4
  • Patients who received platinum-based chemotherapy with good response may benefit from platinum rechallenge upon progression after subsequent therapies 2

Emerging Evidence and Future Directions

• The treatment landscape for metastatic urothelial cancer is rapidly evolving with multiple clinical trials ongoing 4
• The shift toward maximizing efficacy at the initial treatment stage with combinations like EV+P represents a paradigm shift in management 3
• For patients who progress after all available therapies, clinical trials should be considered 5