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

PURPOSE 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 ( FGFR) 1-3 were treated with AZD4547, an oral FGFR1-3 inhibitor. METHODS Patients’ tumors were screened by next-generation sequencing for predefined FGFR 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. RESULTS Between July 2016 and June 2017, 70 patients were assigned and 48 received protocol therapy and are eligible for analysis. Patients’ tumors harbored FGFR1 or FGFR2 amplification (n = 20), FGFR2 or FGFR3 single-nucleotide variants (n = 19), or FGFR1 or FGFR3 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 FGFR1-3 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 FGFR fusions, the response rate was 22% (90% CI, 4.1% to 55%), and 6-month PFS rate was 56% (90% CI, 31% to 100%). CONCLUSION Preliminary signals of activity appeared to be limited to cancers harboring FGFR activating mutations and fusions, although AZD4547 did not meet the primary end point. Different FGFR somatic alterations may confer different levels of signaling potency and/or oncogene dependence.

Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma

“…Molecular profiling has significantly improved diagnosis and prognostic prediction of pediatric brain tumors and has therefore already been implemented in the current as well as the upcoming WHO classification of tumors of the central nervous system (CNS) [ 1 ]. Gene fusions, including the neurotrophic tyrosine kinase ( NTRK ) family or c-ros oncogene 1 ( ROS1 ), are relatively rare, yet their therapeutic impact has been proven in multiple solid tumor types [ 2 , 3 , 4 ]. NTRK gene fusions occur with a prevalence of less than 1% across all tumor types [ 5 , 6 ].…”

A case of different gene mutations in primary and metastatic lesions after EGFR-TKI treatment of lung cancer

“…16 A phase II study of AZD4547 in patients with FGFR fusions is underway. 17 Patients with EGFR-TKIs who acquire resistance via these rare mechanisms may benefit from targeted drugs.…”

FGFR Fusions in Cancer: From Diagnostic Approaches to Therapeutic Intervention

“…The 6-month PFS rate was low for patients with FGFR amplifications (0%) and for patients carrying FGFR mutations (6%) and higher for patients with FGFR fusions (56%). Three of nine patients with FGFR fusions had a PFS > 10 months [63]. In a multicenter, open label, phase II study on infigratinib in chemotherapy-refractory advanced or metastatic cholangiocarcinoma with FGFR alterations, including 48 FGFR2 fusions, all responsive cases harbored FGFR2 fusions [64].…”

“…The majority of FGFR selective inhibitors are under evaluation in clinical trials in which only patients harboring FGFR genomic alterations are enrolled (Table 4). In a phase II trial of AZD4547 in patients with advanced cancers with FGFR1-3 aberrations, PRs were observed in 4 of 48 (8%) patients, including 2 patients with FGFR mutations and 2 with FGFR3-TACC3 fusions [63]. The estimated median PFS was 3.4 months.…”