First-Line Management of Metastatic Urothelial Cancer

Current Treatment Algorithm

The European Association of Urology recommends enfortumab vedotin plus pembrolizumab as the preferred first-line treatment for metastatic urothelial carcinoma, demonstrating a significant improvement in overall survival (OS) compared to platinum-based chemotherapy (31.5 months vs 16.1 months; HR 0.47) 1
The American Society of Clinical Oncology suggests that enfortumab vedotin plus pembrolizumab has a higher objective response rate (67.7% vs 44.4%) with a favorable safety profile compared to chemotherapy 1
The European Society for Medical Oncology notes that grade 3 treatment-related adverse events were lower with enfortumab vedotin plus pembrolizumab (55.9%) compared to platinum-based chemotherapy (69.5%) 1
For cisplatin-eligible patients, the National Comprehensive Cancer Network recommends cisplatin-based combination chemotherapy (gemcitabine plus cisplatin), which has a median OS of approximately 13 months 2
The American Urological Association suggests that cisplatin-based combination chemotherapy should be followed by maintenance avelumab for patients who achieve stable disease or better 3
For cisplatin-ineligible patients, the European Association of Urology recommends carboplatin-based chemotherapy (carboplatin plus gemcitabine), which should also be followed by maintenance avelumab for non-progressing patients 4

The American Society of Clinical Oncology recommends maintenance avelumab for patients who achieve stable disease or better with platinum-based chemotherapy, which significantly improves OS (21.4 vs 14.3 months; HR 0.69) 4
The European Society for Medical Oncology suggests that maintenance avelumab should be started within 10 weeks of completing first-line chemotherapy 4

The National Comprehensive Cancer Network notes that performance status, renal function, and comorbidities should guide treatment selection, with approximately 40% of patients not fit for cisplatin-containing therapy due to poor performance status, impaired renal function, or comorbidities 5
The American Urological Association recommends PD-L1 testing for patients ineligible for platinum-based therapy 6
The European Association of Urology suggests that FGFR3 mutation testing should be considered for potential second-line treatment with erdafitinib 4

The European Association of Urology recommends avelumab first-line maintenance therapy plus best supportive care as a standard of care for patients with locally advanced or metastatic urothelial carcinoma who achieve disease control following first-line platinum-based chemotherapy, demonstrating a significant overall survival benefit 7, 8
Avelumab maintenance therapy prolonged survival without compromising quality of life, with a hazard ratio for overall survival of 0.69 (95% CI: 0.56-0.86; p=0.001) 7, 8

The most frequent adverse reactions in patients receiving avelumab + BSC were fatigue (35%) 8, musculoskeletal pain (29%) 8, and rash (25%) 7
Immune-related adverse events required prompt recognition and management with corticosteroids, with 9% of patients requiring oral prednisone dose equivalent to ≥40 mg daily for immune-mediated adverse reactions 9, 10

Avelumab first-line maintenance should be offered to all patients with locally advanced or metastatic urothelial carcinoma who achieve stable disease or better with platinum-based chemotherapy and have no contraindications to immunotherapy, with treatment initiated within 4-10 weeks after completing chemotherapy 7
The European Society for Medical Oncology recommends enfortumab vedotin plus pembrolizumab as the preferred first-line option for eligible patients, while avelumab maintenance remains the standard approach for patients who receive first-line platinum-based chemotherapy 7