NCI-MATCH is a nationwide, histology-agnostic, signal-finding, molecular profile-driven trial for patients with refractory cancers, lymphomas, or myelomas. Patients with tumors harboring actionable aberration(s) in fibroblast growth factor receptor ( ) were treated with AZD4547, an oral FGFR1-3 inhibitor. Patients' tumors were screened by next-generation sequencing for predefined amplification, activating mutations, or fusions. Patients were treated with AZD4547, 80 mg orally twice daily until progression of disease or drug intolerance. A response rate of 16% was considered promising. Between July 2016 and June 2017, 70 patients were assigned and 48 received protocol therapy and are eligible for analysis. Patients' tumors harbored or amplification (n = 20), or single-nucleotide variants (n = 19), or or fusions (n = 9). The most common primary tumors were breast (33.3%), urothelial (12.5%), and cervical cancer (10.4%).Grade 3 adverse events were consistent with those described in previous clinical trials. Confirmed partial responses were seen in 8% (90% CI, 3% to 18%) and were observed only in patients whose tumors harbored point mutations or fusions. Stable disease was observed in 37.5% (90% CI, 25.8% to 50.4%). The median progression-free survival (PFS) was 3.4 months, and the 6-month PFS rate was 15% (90% CI, 8% to 31%). For patients with tumors harboring fusions, the response rate was 22% (90% CI, 4.1% to 55%), and 6-month PFS rate was 56% (90% CI, 31% to 100%). Preliminary signals of activity appeared to be limited to cancers harboring activating mutations and fusions, although AZD4547 did not meet the primary end point. Different somatic alterations may confer different levels of signaling potency and/or oncogene dependence.