A phase 2 trial of neoadjuvant futibatinib plus durvalumab for cisplatin-ineligible patients with <i>FGFR</i> overexpressing muscle-invasive bladder cancer.

TPS899 Background: There is an unmet need to develop neoadjuvant therapies for cisplatin-ineligible patients (pts) with muscle-invasive bladder cancer (MIBC). Neoadjuvant immune checkpoint inhibition (ICI) has shown promising early results in this population; however, &gt; 2/3 pts did not achieve pathological complete response (pCR), a surrogate endpoint for improved survival. Fibroblast growth factor receptor inhibitor (FGFRi) may induce synergy with ICI through modulation of the tumor immune microenvironment. FGFR mRNA overexpression by RNA in situ hybridization (ISH) is an emerging biomarker that may predict responses to an FGFRi ± ICI. Futibatinib (FUTI) is an irreversible pan-FGFRi, and durvalumab (DURV) is an anti-PD-L1 antibody. Methods: This is a phase 2, single arm, multicenter study to evaluate the efficacy and safety of neoadjuvant FUTI + DURV before cystectomy. Pts with stage cT2 to cT4aN0M0, urothelial carcinoma predominant histology, cisplatin-ineligible by Galsky criteria, and FGFR1-3 mRNA expression ≥3+ by RNAscope ISH assay are eligible. Twenty-four pts will be treated with FUTI 20 mg PO daily and DURV 1500 mg IV on day 1 of every 28-day cycle for 3 cycles. The primary outcome is pCR (defined as ypT0N0). We hypothesize that FUTI + DURV will improve the pCR rate from 21% to 41%. This trial has 80% power to detect the alternative hypothesis while maintaining a one-sided α = 0.1. The study will begin with a safety lead-in period, during which 6 pts will be enrolled for dose-limiting toxicity (DLT) evaluations. After confirming safety (≤ 2 DLTs), another 18 pts will be enrolled. The study will be monitored for futility using a Bayesian Optimal Phase II design, including 2 interim analyses (12 and 18 pts). If there are ≥ 3 pCRs among the first 12 pts, we will continue enrollment. If there are ≥ 5 pCRs among the first 18 pts, the study will continue. When 24 evaluable pts are enrolled, we will reject the null hypothesis and conclude that the treatment is acceptable if there are ≥ 8 pCRs. The secondary endpoints include safety, pathologic downstaging rate, progression-free survival, and overall survival. Correlative studies will explore immune and molecular predictors of response and resistance in the tumor, blood, and urine. Clinical trial information: NCT06263153 .