Targeted and Immunotherapy Advances Offer New Hope for Aggressive Upper Tract Urothelial Carcinoma

Upper tract urothelial carcinoma (UTUC) is a rare and aggressive form of urothelial cancer (UC), representing only 5% to 10% of cases but often presenting with invasive disease, which leads to poorer survival rates, according to an article published in Cancer Management and Research.

“This review summarises the evidence available on UTUC as a disease entity, discusses treatment in perioperative and metastatic settings, and considers future directions for the management of patients diagnosed with UTUC,” wrote Elizabeth Nally, Barts Cancer Institute, Queen Mary University of London in London, UK and coauthors.

Diagnosing UTUC is challenging due to limited tissue access and potential for misdiagnosis. Standard risk factors include tobacco exposure, but certain unique factors, such as aristolochic acid (found in some traditional medicines), elevate UTUC risk, especially in regions such as Taiwan, where incidence is high. Genetic predispositions are also notable, with 10%-20% of UTUC cases associated with hereditary non-polyposis colorectal carcinoma (HNPCC) or Lynch syndrome, prompting guidelines to recommend genetic testing for younger patients with family histories of HNPCC-associated cancers.

The molecular landscape of UTUC is increasingly understood through next-generation sequencing (NGS), revealing distinct genetic mutations compared to bladder UC. High-grade UTUC frequently shows fibroblast growth factor 3 (FGFR3) mutations, offering a promising target for emerging therapies such as erdafitinib, an FGFR inhibitor recently approved after showing a significant survival advantage in the THOR trial for patients with UC with FGFR alterations (HR 0.64; 95% CI, 0.47-0.88). The THOR study also highlighted even greater efficacy in the UTUC subgroup (HR 0.34; 95% CI, 0.18-0.64), indicating unique molecular factors driving UTUC responses.

Treatment for locally advanced UTUC typically involves surgical intervention; but the POUT trial has shifted guidelines by supporting adjuvant chemotherapy with gemcitabine and cisplatin, showing a 3-year disease-free survival (DFS) of 71% versus 46% for surveillance (HR 0.45; 95% CI, 0.38-0.68). However, questions remain, especially regarding cisplatin alternatives like carboplatin, which showed less benefit in DFS in the POUT study.

In metastatic UTUC, immune checkpoint inhibitors (ICI) offer new avenues but lack robust data. Trials like CheckMate 274 and IMvigor130 show mixed efficacy, suggesting that FGFR3-driven UTUC, often “immunologically cold” with low PD-L1 expression, may respond differently to ICIs. Nonetheless, enfortumab vedotin, an antibody-drug conjugate (ADC), is showing promise, doubling overall survival when combined with pembrolizumab compared to chemotherapy in the EV-302 trial.

“Targeted therapy has been shown to be effective and FGFR testing is recommended for all patients diagnosed with UC,” concluded the study authors. “As UTUCs express a greater frequency of FGFR alterations, pan-FGFR inhibitors are likely to benefit more patients with UTUCs.”

Reference

Nally E, Young M, Chauhan V, et al. Upper tract urothelial carcinoma (UTUC): prevalence, impact and management challenge. Cancer Manag Res. 2024;16:467-475. doi:10.2147/CMAR.S445529