Efficacy and safety of fexagratinib (Fexa) in combination with tislelizumab (T) in a phase II study of patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC) harboring FGFR alterations (FGFRa).

789 Background: A significant proportion of pts with mUC are intolerant to platinum-based chemotherapy, highlighting the urgent need for alternatives. Fexagratinib(former AZD4547)is a potent and selective inhibitor of FGFR and had showed promising anti-tumor activity in mUC pts with FGFRa. This Phase II study (NCT05775874) aimed to evaluate efficacy of Fexa plus T combination treatment (Tx) in mUC pts harboring FGFRa who were 1st-line platinum-ineligible or rejected chemotherapy. Methods: FGFR3 mRNA overexpression were detected by in situ hybridization (RNAscope). FGFR3 activating mutations or fusions were detected by NGS. Eligible pts received continuous oral Fexa 80mg BID plus T 200 mg infusion on day 1 of a 21-day cycle. Primary objectives were objective response rate (ORR) by Independent Review Committee (IRC) per RECIST 1.1. Results: As of data cut off (10 Aug 2024), 26 pts received combination Tx with the majority being treatment-naïve. Of those, 57.7% were male with median age of 68.5 years and 86% had an ECOG of 1. Nine pts had confirmed FGFR3 mutation or fusion and 24 pts were overexpression. In 22 pts with available PD-L1 expression status, 86.4% were negative (CPS<10). Among 24 IRC evaluable pts, 9 (37.5%) partial responses (PRs) were confirmed. The median duration of response was 5.9 months. The median progression free survival mPFS was 5.3 months (95%CI 2.7-8.2) with 4 pts were still on Tx. Among the evaluable pts with FGFR3 overexpression but without mutation/fusion, ORR was37.5%,(6/16)pts.Most common treatment-related adverse events (TRAEs) were stomatitis (42%), anemia (38.5%), AST/ALT increased (27%). Grade ≥3 TRAEs occurred in 12 (46.2%) pts, incidence >10% events included stomatitis (n=3, 12%), hand-foot syndrome(n=3, 12%). Immune-related AEs occurred in 23.0% of pts. The majority of TRAEs were reversible. Conclusions: 1st-line Tx with Fexa plus T were tolerable with a safety profile consistent with previously reported for both agents. The toxicity was overall manageable. Encouraging efficacy was observed in pts with FGFR3 overexpression, regardless of PD-L1 expression or FGFR3 mutations/fusions.Further exploration of these findings is warranted. Clinical trial information: NCT05775874 .