What is the next step in treatment for metastatic urothelial cancer after progression on gemcitabine and cisplatin with normal Glomerular Filtration Rate (GFR)?

Treatment for Metastatic Urothelial Cancer After Gemcitabine and Cisplatin with Normal GFR

Pembrolizumab is the preferred second-line treatment for metastatic urothelial carcinoma after progression on gemcitabine and cisplatin in patients with normal GFR. 1

First-Line Treatment Recap

• Gemcitabine plus cisplatin (GC) is the standard first-line treatment for platinum-fit patients with metastatic urothelial carcinoma 2
• Normal GFR indicates the patient remains platinum-fit, which is important for subsequent treatment decisions 2

Second-Line Treatment Options

Preferred Option: Pembrolizumab

• Pembrolizumab has strong evidence (category 1) showing improved overall survival compared to chemotherapy with a median OS of 10.3 months 1
• Pembrolizumab demonstrated significantly fewer grade 3-5 adverse events (15.0% vs 49.4%) compared to chemotherapy 1, 3
• The overall response rate to pembrolizumab is 21-29%, with a complete response rate of 7-10% 1
• Treatment should continue until disease progression or unacceptable toxicity 3

Alternative Immune Checkpoint Inhibitors

• Other FDA-approved ICIs such as atezolizumab, nivolumab, durvalumab, and avelumab are approved options but with lower evidence level (category 2) than pembrolizumab 1
• These alternatives may be considered if pembrolizumab is not tolerated or contraindicated 2

Third-Line Treatment Options (After Progression on Immunotherapy)

Enfortumab Vedotin

• Enfortumab vedotin is strongly recommended for patients who have progressed on both platinum-containing chemotherapy and immunotherapy 2
• This antibody-drug conjugate has shown significant survival benefit in the third-line setting 2

FGFR Inhibitors for Specific Genetic Alterations

• For patients with FGFR2/3 genetic alterations, erdafitinib is recommended after progression on platinum chemotherapy and immunotherapy 2, 1
• Testing for FGFR2/3 genetic alterations should be carried out for potential use of erdafitinib 2
• This is particularly relevant as FGFR3 alterations are common in urothelial carcinoma 2

Chemotherapy Options

• If immunotherapy is not suitable or has failed, alternative chemotherapy options include docetaxel, paclitaxel, or vinflunine 2
• Vinflunine should only be offered if immunotherapy or combination chemotherapy is not feasible 2

Emerging Treatment Options

• Sacituzumab govitecan is being investigated in clinical trials and may be an option for patients who have exhausted standard therapies 2
• Enrollment in clinical trials is strongly recommended for subsequent-line therapy when appropriate 1

Treatment Algorithm

1. First-line: Gemcitabine + cisplatin (already received)
2. Second-line: Pembrolizumab (preferred) 1, 3
3. Third-line options:
   • Enfortumab vedotin (if progression on immunotherapy) 2
   • Erdafitinib (if FGFR2/3 alterations present) 2, 1
   • Alternative chemotherapy (docetaxel, paclitaxel, vinflunine) 2
4. Fourth-line: Clinical trials or novel agents (e.g., sacituzumab govitecan) 2

Monitoring and Management

• Regular assessment of treatment response using appropriate imaging 2
• Monitoring for immune-related adverse events with pembrolizumab, which may require systemic glucocorticoids 3
• Assessment of quality of life, as treatment of metastatic bladder cancer has significant impact on health-related QoL 2

Common Pitfalls to Avoid

• Delaying immunotherapy in the second-line setting, as it has proven survival benefit 1
• Failing to test for FGFR2/3 alterations, which could identify patients eligible for targeted therapy 2
• Overlooking the potential for maintenance avelumab if used in first-line setting, which would change the second-line approach 2