Phase II Study of AZD4547 in Patients With Tumors Harboring Aberrations in the FGFR Pathway: Results From the NCI-MATCH Trial (EAY131) Subprotocol W.

Abstract

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 (<i>FGFR</i>) <i>1-3</i> were treated with AZD4547, an oral FGFR1-3 inhibitor. Patients' tumors were screened by next-generation sequencing for predefined <i>FGFR</i> 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 <i>FGFR1</i> or <i>FGFR2</i> amplification (n = 20), <i>FGFR2</i> or <i>FGFR3</i> single-nucleotide variants (n = 19), or <i>FGFR1</i> or <i>FGFR3</i> 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 <i>FGFR1-3</i> 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 <i>FGFR</i> 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 <i>FGFR</i> activating mutations and fusions, although AZD4547 did not meet the primary end point. Different <i>FGFR</i> somatic alterations may confer different levels of signaling potency and/or oncogene dependence.