Fibroblast growth factor receptor 3 (FGFR3) alterations and response to immune checkpoint inhibition in metastatic urothelial carcinoma: A systematic review and meta-analysis.

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Background: Immune checkpoint inhibitors (ICIs) have become a cornerstone in the treatment of metastatic urothelial carcinoma (mUC). Fibroblast growth factor receptor 3 (FGFR3) alterations, present in up to 20% of mUC patients, have been proposed as a potential biomarker influencing response to ICIs, supported by preclinical evidence suggesting that FGFR3-driven tumors exhibit a T-cell-depleted tumor microenvironment, potentially limiting ICIs efficacy. This systematic review and meta-analysis aimed to evaluate the association between FGFR3 alterations and treatment response and survival outcomes in patients with mUC treated with ICIs. Methods: A systematic literature search was conducted from database inception to 10 November 2025 to identify studies reporting outcomes of immune checkpoint inhibitor therapy in metastatic urothelial carcinoma stratified by FGFR3 alteration status. Databases searched included PubMed/MEDLINE, Embase, CENTRAL, Web of Science, Scopus and Cochrane Central Register of Controlled Trials. Eligible studies comprised prospective or retrospective cohort studies, phase I–III clinical trials, and registry-based analyses of adult patients with mUC receiving ICIs, with outcomes reported by FGFR3 status, with outcomes stratified by FGFR3 status. Key outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Pooled effect estimates were calculated using random-effects models, with subgroup analyses were performed according to treatment line. Results: Fifteen studies involving 2,179 eligible patients with mUC treated with ICIs were included. ORRs were comparable between FGFR3-altered and wild-type tumours (RR 0.82 95% CI 0.63-1.07). In contrast, FGFR3-altered tumors demonstrated a significantly lower DCR compared with FGFR3 wild-type tumors (RR 0.75, 95% CI 0.57-0.96), particularly in second-line or later treatment settings (RR 0.58, 95% CI 0.41–0.82). FGFR3 alterations were significantly associated with inferior OS (HR 1.25, 95% CI 1.08–1.44) and PFS (HR 1.63, 95% CI 1.23–2.16). The association with poorer OS was stronger in second-line or later treatment settings (HR 1.70, 95% CI 1.18-2.44). Conclusions: FGFR3 alterations in mUC are associated with inferior disease control and poorer survival outcomes in patients treated with ICIs. These findings support FGFR3 alterations as a negative prognostic marker in the immunotherapy setting and highlight the potential role of therapeutic strategies combining FGFR inhibition with immunotherapy to optimize outcomes in FGFR-altered mUC.