What are the second-line therapy options for metastatic urothelial carcinoma after progression on gemcitabine (Gemzar) and cisplatinum (Platinol)?

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

Pembrolizumab is 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. 1

Immune Checkpoint Inhibitors (ICIs)

• Pembrolizumab: First choice with category 1 evidence from phase III trials showing longer median overall survival (10.3 vs 7.4 months) compared to chemotherapy and fewer grade 3-5 adverse events (15.0% vs 49.4%) 1

• Other FDA-approved ICIs: Atezolizumab, nivolumab, durvalumab, and avelumab are all approved as second-line options after platinum-based chemotherapy, but with category 2 evidence (lower than pembrolizumab's category 1) 1

• PD-L1 testing: While PD-L1 expression correlates with higher response rates, durable responses occur even in patients with low PD-L1 expression. Testing is not required for second-line therapy after platinum failure 1

Alternative Options When ICIs Are Not Suitable

• Chemotherapy options: Docetaxel, paclitaxel, gemcitabine monotherapy, or combination regimens like gemcitabine/paclitaxel may be considered 1

• Targeted therapies:

  • Erdafitinib for patients with FGFR2/3 genetic alterations 1
  • Enfortumab vedotin for patients who have progressed on both platinum chemotherapy and immunotherapy 1

Treatment Algorithm Based on Prior Therapy

1. First-line with gemcitabine/cisplatin → Pembrolizumab (preferred, category 1) 1
2. If progression on pembrolizumab → Consider enfortumab vedotin 1
3. If FGFR2/3 alterations present → Consider erdafitinib 1

Efficacy of Pembrolizumab in Second-Line Setting

• Overall response rate: 21-29% 1, 2
• Complete response rate: 7-10% 1, 2
• Median overall survival: 10.3 months 1
• Median duration of response: Not reached in some studies, indicating durable responses 1

Common Adverse Events with Pembrolizumab

• Grade 3-4 treatment-related adverse events: 15-18% 1, 2
• Most common adverse events: Fatigue (38%), musculoskeletal pain (32%), pruritus (23%), and rash (20%) 2
• Immune-related adverse events: May require systemic glucocorticoids in approximately 8% of patients 2

Special Considerations

• Clinical trial enrollment: Strongly recommended for subsequent-line therapy when appropriate 1

• Palliative radiation: Can be combined with chemotherapy for metastases or pelvic recurrence after cystectomy. Radiosensitizing options include cisplatin (category 2A), docetaxel/paclitaxel (category 2B), or low-dose gemcitabine (category 2B) 1

• Treatment sequencing: With multiple new agents available, optimal sequencing beyond second-line remains unclear and should be based on prior treatments received 1

• Monitoring: Tumor assessments typically performed at 9 weeks after first dose, then every 6 weeks for first year, and every 12 weeks thereafter 2

The landscape of metastatic urothelial carcinoma treatment has evolved significantly with the introduction of immune checkpoint inhibitors, offering improved survival and quality of life compared to traditional chemotherapy options after platinum-based regimen failure.