Second-Line Therapy for Metastatic Urothelial Carcinoma After Gemcitabine and Cisplatin

Immune Checkpoint Inhibitors (ICIs)

The National Comprehensive Cancer Network recommends pembrolizumab as the preferred second-line therapy for metastatic urothelial carcinoma after progression on gemcitabine and cisplatin, based on category 1 evidence showing improved overall survival compared to chemotherapy, with a median overall survival of 10.3 months and fewer grade 3-5 adverse events (15.0% vs 49.4%) 1, 2
Other FDA-approved ICIs, such as atezolizumab, nivolumab, durvalumab, and avelumab, are approved as second-line options after platinum-based chemotherapy, but with category 2 evidence (lower than pembrolizumab's category 1) 4, 2

The National Comprehensive Cancer Network suggests chemotherapy options, such as docetaxel, paclitaxel, gemcitabine monotherapy, or combination regimens like gemcitabine/paclitaxel, may be considered for patients who are not suitable for ICIs 5
Erdafitinib is recommended for patients with FGFR2/3 genetic alterations, based on evidence from the European Urology journal 2, 6
Enfortumab vedotin is recommended for patients who have progressed on both platinum chemotherapy and immunotherapy, based on evidence from the European Urology journal 6, 7

The treatment algorithm recommends pembrolizumab as the first choice for second-line therapy after gemcitabine/cisplatin, with category 1 evidence 1, 2
If progression on pembrolizumab, consider enfortumab vedotin, based on evidence from the European Urology journal 6, 7
If FGFR2/3 alterations are present, consider erdafitinib, based on evidence from the European Urology journal 2, 6

The overall response rate to pembrolizumab is 21-29%, with a complete response rate of 7-10% and a median overall survival of 10.3 months 1, 3

Clinical trial enrollment is strongly recommended for subsequent-line therapy when appropriate, based on evidence from the National Comprehensive Cancer Network 5
Palliative radiation can be combined with chemotherapy for metastases or pelvic recurrence after cystectomy, with radiosensitizing options including cisplatin, docetaxel/paclitaxel, or low-dose gemcitabine 1, 5
Treatment sequencing beyond second-line remains unclear and should be based on prior treatments received, based on evidence from the European Urology journal 6, 8