What are the first‑line treatment options for advanced or metastatic urothelial carcinoma in a platinum‑eligible patient?

First-Line Treatment for Advanced/Metastatic Urothelial Cancer in Cisplatin-Ineligible Patients

For cisplatin-ineligible patients with advanced or metastatic urothelial carcinoma, enfortumab vedotin plus pembrolizumab is the preferred first-line treatment, delivering a median overall survival of 31.5 months compared to 16.1 months with platinum-based chemotherapy (HR 0.47). 1, 2, 3

Primary Treatment Recommendation

Enfortumab vedotin plus pembrolizumab should be offered as the standard first-line therapy for all cisplatin-ineligible patients with advanced urothelial carcinoma, regardless of PD-L1 status. 1, 2, 3

• This combination achieves an objective response rate of 67.7% versus 44.4% with chemotherapy, with progression-free survival of 12.5 months versus 6.3 months (HR 0.45). 1, 3
• Grade 3+ treatment-related adverse events occur in 55.9% of patients, which is actually lower than the 69.5% rate with platinum-based chemotherapy. 1, 3
• The ESMO-MCBS score is 4, indicating the highest magnitude of clinical benefit. 1, 3
• This regimen is effective in both cisplatin-eligible and cisplatin-ineligible patients, making it the universal first-line standard. 3, 4

Alternative Treatment Options When Enfortumab Vedotin Plus Pembrolizumab Is Unavailable

For Carboplatin-Eligible Patients

Carboplatin plus gemcitabine followed by maintenance avelumab is the recommended alternative for patients who cannot receive enfortumab vedotin plus pembrolizumab but are eligible for carboplatin. 2, 3, 5

• Carboplatin-based regimens are inferior to cisplatin-based therapy but remain appropriate for cisplatin-ineligible patients. 3, 5
• Maintenance avelumab must be initiated within 4-10 weeks after completing chemotherapy in patients achieving stable disease or better. 2, 3
• Avelumab maintenance provides an overall survival of 21.4 months versus 14.3 months with best supportive care alone (HR 0.69), representing an 8.8-month survival gain. 1, 2, 3

For Patients Ineligible for Any Platinum-Based Chemotherapy

Pembrolizumab monotherapy is recommended for patients who cannot receive any platinum-based chemotherapy (neither cisplatin nor carboplatin). 1, 6, 7

• In the KEYNOTE-052 trial of 370 cisplatin-ineligible patients, pembrolizumab monotherapy achieved an objective response rate of 29%, with 10% complete responses. 1, 6
• Median overall survival was 11.5 months overall, but reached 18.5 months in patients with PD-L1 combined positive score (CPS) ≥10. 1, 6
• Grade 3-4 treatment-related adverse events occurred in only 18% of patients. 1, 6

Atezolizumab monotherapy is an alternative to pembrolizumab for platinum-ineligible patients. 1, 7

• In the IMvigor210 trial, atezolizumab achieved an objective response rate of 23-24% with median overall survival of 15.9-16.3 months. 1
• Grade 3-4 treatment-related adverse events occurred in 16% of patients. 1

Defining Cisplatin Ineligibility

Patients are considered cisplatin-ineligible if they meet one or more of the following criteria: 1, 3, 7

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

Approximately 40-50% of patients with metastatic urothelial carcinoma are cisplatin-ineligible due to these factors. 1, 8

Critical Management Considerations

FGFR2/3 genetic alterations should be tested in all patients with advanced disease at diagnosis to identify potential candidates for erdafitinib in second-line therapy. 3, 4

PD-L1 testing is no longer critical for first-line treatment decisions given the superiority of enfortumab vedotin plus pembrolizumab across all PD-L1 expression levels. 3, 4

Common Pitfalls and How to Avoid Them

• Do not delay treatment initiation for molecular testing results when enfortumab vedotin plus pembrolizumab is planned, as PD-L1 status does not affect treatment selection. 3
• Do not use immune checkpoint inhibitor monotherapy in carboplatin-eligible patients unless they are truly ineligible for all platinum-based therapy, as carboplatin plus gemcitabine followed by avelumab maintenance provides superior outcomes. 2, 5
• Do not skip maintenance avelumab in patients who receive platinum-based chemotherapy and achieve disease control, as this provides a substantial 8.8-month survival benefit. 1, 2, 3
• Ensure avelumab maintenance begins within 4-10 weeks after completing chemotherapy to maximize benefit. 2, 3

Treatment Algorithm Summary

1. First choice: Enfortumab vedotin plus pembrolizumab (regardless of cisplatin eligibility) 1, 2, 3
2. If enfortumab vedotin unavailable and carboplatin-eligible: Carboplatin plus gemcitabine → maintenance avelumab 2, 3, 5
3. If ineligible for all platinum therapy: Pembrolizumab or atezolizumab monotherapy 1, 6, 7