Background: FGFR alterations are observed in approximately 7% of advanced solid malignancies and are associated with poor prognosis and resistance to traditional anti-cancer therapy. Despite this, optimal therapeutic strategies with FGFR inhibitors for most of FGFR-altered solid malignancies are yet to be defined. Circulating tumor DNA (ctDNA) analysis has the potential to accurately detect FGFR alterations by assessing spatial and temporal intratumoral heterogeneity. Methods: We conducted a multicenter, investigator-initiated, phase II basket-type trial, TiFFANY, to evaluate the efficacy and safety of futibatinib, a highly selective covalent pan-FGFR inhibitor, in patients (pts) with advanced solid malignancies with FGFR alterations identified by ctDNA analysis who were refractory or intolerant to standard-of-care treatment. ctDNA analysis was performed in the GOZILA study. Enrolled pts received futibatinib at a dose of 20 mg once daily in a 21 day-cycle. The primary endpoint was investigator-assessed objective response rate (ORR). We set the threshold ORR of 5% and expected one of 25%. Planned sample size was 26 with one-sided alpha of 2.5% and power of 80%. Blood and tissue samples collected before treatment (baseline), at week 3, and after disease progression were analyzed for biomarkers and resistance mechanisms. Results: Twenty-six pts with FGFR alterations (mutation, 9; amplification, 13; fusion, 4) in ctDNA were enrolled between August 2019 and March 2021. The primary endpoint was met with five (19.2%; 95% CI, 6.6–39.4%) achieving a confirmed partial response (PR) in various cancer types (biliary tract, gastric, urothelial, and urachal cancer). Median progression-free survival and overall survival were 2.6 and 8.9 months. The most common treatment-associated adverse events were hyperphosphatemia (100%), eye toxicity (46.2%) and diarrhea (42.3%), all of which were manageable. The median proportional change in ctDNA fraction from baseline to 3 weeks after treatment initiation in pts who achieved PR was significantly less than in pts with stable or progressive disease (0.11 vs. 1.0 vs. 1.6, respectively). Pts with no concurrent RTK/RAS/PI3K and cell cycle alterations in ctDNA were significantly more likely to respond to futibatinib than those with at least one of these alterations (ORR 50% vs. 0%; P=0.0038). Acquired gene alterations in ctDNA after progression tended to be more common in pts with FGFR amplification (83.3%) than in those with FGFR mutation or fusion (60% or 66.7%). Conclusions: Futibatinib demonstrated promising efficacy in refractory advanced solid malignancies with FGFR alterations in ctDNA with an acceptable toxicity profile. Oncogenic co-alterations detected by ctDNA genotyping may predict primary resistance. Clinical trial information: JapicCTI-194624.