What is the recommended treatment algorithm for a patient with metastatic urothelial carcinoma of the bladder, including first‑line cisplatin‑based chemotherapy (or carboplatin if cisplatin‑ineligible), subsequent PD‑1/PD‑L1 checkpoint inhibitor immunotherapy, FGFR‑targeted therapy for FGFR2/FGFR3 alterations, and later‑line enfortumab‑vedotin after chemo‑immunotherapy failure?

Treatment Algorithm for Metastatic Urothelial Carcinoma of the Bladder

Enfortumab vedotin plus pembrolizumab is now the preferred first-line treatment for all patients with metastatic urothelial carcinoma, regardless of cisplatin eligibility or PD-L1 status, delivering a median overall survival of 31.5 months compared to 16.1 months with platinum-based chemotherapy. 1, 2

First-Line Treatment Selection

Preferred Regimen for All Patients

• Enfortumab vedotin 1.25 mg/kg on Days 1 and 8 plus pembrolizumab 200 mg on Day 1 of each 21-day cycle is the only Category 1, preferred first-line regimen for both cisplatin-eligible and cisplatin-ineligible patients 1
• This combination achieves an objective response rate of 67.7% versus 44.4% with chemotherapy, with progression-free survival of 12.5 months versus 6.3 months (HR 0.45) 1, 2
• Grade 3+ treatment-related adverse events occur in 55.9% of patients, which is lower than the 69.5% rate with platinum-based chemotherapy 2
• No PD-L1 testing is required for this indication 1

Alternative First-Line Options When Enfortumab Vedotin + Pembrolizumab Is Unavailable

For cisplatin-eligible patients:

• Gemcitabine/cisplatin (GC) or dose-dense MVAC with growth factor support are preferred platinum-based regimens, achieving median overall survival of approximately 13-15 months 3, 2
• If these patients achieve stable disease or better after 4-6 cycles of platinum chemotherapy, mandatory maintenance avelumab should be initiated within 4-10 weeks, providing median overall survival of 21.4 months versus 14.3 months with best supportive care (HR 0.69) 2

For cisplatin-ineligible but carboplatin-eligible patients:

• Gemcitabine/carboplatin followed by maintenance avelumab (if stable disease or better is achieved) 3, 2
• Carboplatin-based regimens show response rates of 26-42% but are inferior to cisplatin-based therapy 3

For patients ineligible for any platinum chemotherapy:

• Pembrolizumab monotherapy achieves an objective response rate of 29% (10% complete responses) with median overall survival of 11.5 months overall and 18.5 months in patients with PD-L1 CPS ≥10 2
• Atezolizumab monotherapy shows objective response rate of 23-24% with median overall survival of 15.9-16.3 months 2
• Grade 3-4 adverse events occur in approximately 16-18% of patients receiving checkpoint inhibitor monotherapy 2

Critical Caveat for Checkpoint Inhibitor Monotherapy

• Do not use pembrolizumab or atezolizumab monotherapy in cisplatin-ineligible patients with low PD-L1 expression (PD-L1 <5% for atezolizumab or CPS <10 for pembrolizumab), as the KEYNOTE-361 and IMvigor130 trials demonstrated decreased survival compared to platinum-based chemotherapy in this population 3

Second-Line Treatment After Platinum-Based Chemotherapy

Preferred Second-Line Options

• Pembrolizumab is the Category 1 recommendation, demonstrating median overall survival of 10.3 months versus 7.4 months with chemotherapy (HR 0.73, P=0.002), with grade 3+ adverse events in only 15.0% versus 49.4% with chemotherapy 3
• Atezolizumab, nivolumab, durvalumab, or avelumab are alternative checkpoint inhibitors, all approved regardless of PD-L1 expression levels 3
• Enfortumab vedotin monotherapy (1.25 mg/kg on Days 1,8, and 15 of a 28-day cycle) achieves confirmed objective response rate of 44% with median overall survival of 12.88 months versus 8.97 months with chemotherapy 3, 1

FGFR-Targeted Therapy

• Erdafitinib is recommended for patients with FGFR3 or FGFR2 genetic alterations (confirmed by FDA-approved testing), achieving confirmed objective response rate of 40% with median overall survival gain of 4.3 months (HR 0.64) 3, 4, 2
• Erdafitinib can be used as second-line therapy after first-line checkpoint inhibitor or as third-line therapy after both platinum and checkpoint inhibitor 3, 4

Third-Line and Subsequent Treatment

After Failure of Enfortumab Vedotin + Pembrolizumab First-Line

• Platinum rechallenge is preferred if the patient had a platinum-free interval of ≥6-12 months and remains platinum-eligible, achieving disease control rates of approximately 57% 4
• Erdafitinib if FGFR2/3 alterations are present 4, 2
• Single-agent chemotherapy options include paclitaxel, docetaxel, or vinflunine, with response rates of 8-30% and median overall survival of 5-7 months 3, 4

After Failure of Platinum and Checkpoint Inhibitor

• Enfortumab vedotin monotherapy is the preferred option if not previously given 3, 5
• Erdafitinib for FGFR-altered tumors 3, 4
• Clinical trial enrollment is strongly recommended at this stage, as data for subsequent-line therapy are highly variable 3, 4

Essential Molecular Testing

• FGFR2/3 genetic alterations should be tested in all patients with advanced disease to identify erdafitinib candidates 3, 2
• PD-L1 testing is only necessary if considering checkpoint inhibitor monotherapy in cisplatin-ineligible patients; it is not required for enfortumab vedotin plus pembrolizumab 3, 1, 2

Cisplatin Eligibility Criteria

Patients are cisplatin-ineligible if they have any of the following:

• Creatinine clearance <60 mL/min 3, 2
• ECOG performance status ≥2 3, 2
• Grade ≥2 hearing loss 2
• Grade ≥2 peripheral neuropathy 2
• NYHA Class III heart failure 2

Approximately 40-50% of patients with metastatic urothelial carcinoma are cisplatin-ineligible 2

Key Toxicity Management

Enfortumab Vedotin-Specific Toxicities

• Rash occurs in 48-49% of patients and peripheral neuropathy in 50%; both require proactive monitoring and dose modifications 1
• Hyperglycemia (Grade 3 in 6.1%) requires baseline screening and management with metformin or insulin 1

Checkpoint Inhibitor Toxicities

• Grade 3+ immune-related adverse events occur in 15-18% of patients receiving checkpoint inhibitor monotherapy 3

Role of Local Therapy

• Palliative radiation therapy is recommended for symptomatic metastatic sites, particularly bone metastases or sites causing pain or obstruction 4
• Surgery or radiotherapy may be feasible in highly select cases for patients with major partial response in a previously unresectable primary tumor or solitary resectable residual disease after chemotherapy 3

Duration of Chemotherapy

• Continue chemotherapy for a maximum of 6 cycles, depending on response 3
• If no response after 2 cycles or significant morbidities occur, change therapy based on performance status, disease extent, and prior therapy 3