Urothelial Carcinoma

Advanced and metastatic urothelial cancer — upper tract disease, FGFR alterations, enfortumab vedotin plus pembrolizumab, and avelumab maintenance

Key Points

• Urothelial carcinoma (UC) encompasses cancers of the bladder, renal pelvis, ureter, and urethra; upper tract UC (UTUC) is associated with Lynch syndrome in ~10–15% of cases.
• Enfortumab vedotin + pembrolizumab (EV+P) is the new preferred first-line standard for advanced/metastatic UC regardless of cisplatin eligibility (EV-302: OS 31.5 vs 16.1 months).
• Erdafitinib targets FGFR2/3 alterations (~20% of advanced UC) and is FDA approved for FGFR-altered UC after platinum-based chemotherapy.
• Avelumab maintenance after first-line platinum chemotherapy (JAVELIN Bladder 100) significantly improves overall survival vs. best supportive care.
• Cisplatin-based regimens (gemcitabine + cisplatin or dose-dense MVAC) remain an option when IO combination is not used or is contraindicated.
• Lynch syndrome (particularly MSH2) strongly predisposes to upper tract urothelial carcinoma; germline testing is recommended for UTUC under age 60.

Upper Tract Urothelial Carcinoma (UTUC)

Upper tract urothelial carcinoma (UTUC) refers to tumors arising in the urothelial lining of the renal pelvis and ureter. UTUC accounts for approximately 5–10% of all urothelial cancers (~7,900 cases/year in the US). It shares histologic and molecular features with bladder urothelial carcinoma but has important clinical distinctions: Hereditary UTUC: • Lynch syndrome is found in ~10–15% of UTUC cases — far higher than the ~3% seen with bladder cancer. MSH2 mutations carry the highest UTUC risk (up to 22% lifetime risk). Germline MMR testing is recommended for all patients with UTUC diagnosed…

Molecular Targets in Urothelial Carcinoma

Advanced urothelial carcinoma has been transformed by the identification of several actionable molecular targets: FGFR alterations (~20% of advanced UC): • FGFR3 mutations (most common: R248C, S249C, G372C, Y375C) and FGFR2/3 fusions drive oncogenesis in a subset of luminal-papillary UC. • Erdafitinib (Balversa): Pan-FGFR tyrosine kinase inhibitor; FDA approved 2019 for FGFR2/3-altered advanced UC after platinum-based chemotherapy (NORSE trial and BLC2001). ORR ~40%, median OS ~11 months. Dose adjusted by serum phosphate levels (a marker of target engagement). Ocular toxicity (RPED, dry eye)…

First-Line Treatment of Advanced/Metastatic UC

The treatment landscape for advanced/metastatic urothelial carcinoma underwent a fundamental shift with the EV-302 trial results: Preferred first-line regimen — EV + Pembrolizumab (EV+P): • EV-302/KEYNOTE-A39 (N=886): Enfortumab vedotin 1.25 mg/kg IV days 1,8 + pembrolizumab 200 mg IV day 1, every 3 weeks. • Results: OS 31.5 vs. 16.1 months (HR 0.47), PFS 12.5 vs. 6.3 months vs. platinum-based chemotherapy. Benefit was consistent regardless of cisplatin eligibility, PD-L1 status, and UTUC vs. bladder primary. • FDA approved April 2024 as first-line treatment for all advanced/metastatic UC.…

Second-Line and Later Treatment

For patients who progress after first-line therapy, treatment selection depends on what was received previously: After EV+P (first-line IO+ADC): • Platinum-based chemotherapy (GC or MVAC): Reasonable option for platinum-naive patients with good PS. • Erdafitinib: For FGFR2/3-altered tumors — test at diagnosis. • Sacituzumab govitecan (Trodelvy — anti-Trop-2 ADC): Active in pretreated UC (TROPHY-U-01, ORR ~27% after platinum + checkpoint inhibitor). After platinum chemotherapy (without prior IO): • Pembrolizumab (KEYNOTE-045): Significantly improved OS vs. chemotherapy in second-line (10.3…