Advanced Urothelial Cancer Management

First-Line Treatment

The European Society for Medical Oncology (ESMO) recommends enfortumab vedotin plus pembrolizumab as the preferred first-line treatment for advanced urothelial carcinoma, delivering a median overall survival of 31.5 months compared to 16.1 months with platinum-based chemotherapy (HR 0.47) 1, 2
Enfortumab vedotin plus pembrolizumab achieves an overall survival of 31.5 months vs 16.1 months with chemotherapy, with a progression-free survival gain of 6.2 months and an objective response rate of 67.7% vs 44.4% with chemotherapy 1, 2
The ESMO-MCBS score for enfortumab vedotin plus pembrolizumab is 4, indicating the highest clinical benefit 1, 2
Grade 3+ treatment-related adverse events occur in 55.9% of patients receiving enfortumab vedotin plus pembrolizumab, which is lower than the 69.5% rate seen with chemotherapy 1, 3

For cisplatin-eligible patients who cannot receive enfortumab vedotin, gemcitabine plus cisplatin (GC) or high-dose MVAC (methotrexate, vinblastine, adriamycin, cisplatin) with G-CSF are strong alternative options 1, 4
For cisplatin-ineligible but carboplatin-eligible patients, carboplatin plus gemcitabine is an appropriate option, although it is inferior to cisplatin-based regimens 1, 4

Avelumab maintenance is mandatory for patients achieving stable disease or better after platinum-based chemotherapy, providing an overall survival gain of 8.8 months and a median OS of 21.4 months vs 14.3 months with best supportive care 1, 2, 4
The ESMO-MCBS score for avelumab maintenance is 4, indicating the highest clinical benefit 1, 2

Enfortumab vedotin is recommended as a second-line treatment option, with an overall survival gain of 3.97 months and an HR of 0.70 vs chemotherapy 1, 2
Erdafitinib is recommended for patients with FGFR2/3 alterations, with an overall survival gain of 4.3 months and an HR of 0.64 vs chemotherapy 1, 2, 4
Sacituzumab govitecan and pembrolizumab are also options for second-line treatment, with ESMO-MCBS scores of 2 and 4, respectively 1, 2

FGFR2/3 genetic alterations should be tested in all patients with advanced disease to identify erdafitinib candidates 1, 4
PD-L1 testing is no longer critical for first-line decisions given the superiority of enfortumab vedotin plus pembrolizumab 1
Cisplatin eligibility criteria include creatinine clearance <60 mL/min, ECOG performance status ≥2, grade ≥2 hearing loss, grade ≥2 neuropathy, and NYHA Class III heart failure 4

For patients progressing after enfortumab vedotin plus pembrolizumab, consider treatments not previously given, such as platinum-based chemotherapy, vinflunine or taxanes, and clinical trials with novel agents 1, 3, 4

Enfortumab vedotin + pembrolizumab is recommended as the standard first‑line therapy for all cisplatin‑ineligible patients with advanced urothelial carcinoma, providing a median overall survival of ~31.5 months versus 16.1 months with platinum‑based chemotherapy (HR 0.47)【5】.
The combination achieves an objective response rate of ~68 % and a progression‑free survival of 12.5 months, compared with 44 % response and 6.3 months PFS for chemotherapy (HR 0.45)【5】.
Grade 3 or higher treatment‑related adverse events occur in ~56 % of patients receiving the combination, lower than the ~70 % observed with platinum‑based regimens【5】.
The regimen receives an ESMO‑MCBS score of 4, indicating a high magnitude of clinical benefit【5】.

For patients who cannot receive enfortumab vedotin + pembrolizumab but are eligible for carboplatin, carboplatin + gemcitabine followed by maintenance avelumab is advised; maintenance avelumab should start within 4–10 weeks after chemotherapy completion in patients with stable disease or better【5】.
Maintenance avelumab 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【5】.

Pembrolizumab monotherapy is recommended for patients ineligible for any platinum chemotherapy, achieving an objective response rate of 29 % (including 10 % complete responses) in a cohort of 370 cisplatin‑ineligible patients【6】【7】.
Median overall survival with pembrolizumab is 11.5 months overall and extends to 18.5 months in patients with PD‑L1 CPS ≥ 10【6】.
Grade 3‑4 treatment‑related adverse events occur in ~18 % of patients receiving pembrolizumab monotherapy【7】.
Atezolizumab monotherapy is an alternative, showing an objective response rate of 23‑24 % and median overall survival of 15.9‑16.3 months【6】【7】.
Grade 3‑4 adverse events with atezolizumab occur in ~16 % of patients【7】.

Approximately 40‑50 % of patients with metastatic urothelial carcinoma are cisplatin‑ineligible due to reduced renal function, poor performance status, significant hearing loss, peripheral neuropathy, or advanced cardiac disease【6】【8】.