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Ref Type Journal Article
PMID (32463741)
Authors Chae YK, Hong F, Vaklavas C, Cheng HH, Hammerman P, Mitchell EP, Zwiebel JA, Ivy SP, Gray RJ, Li S, McShane LM, Rubinstein LV, Patton D, Williams PM, Hamilton SR, Mansfield A, Conley BA, Arteaga CL, Harris LN, O'Dwyer PJ, Chen AP, Flaherty KT
Title Phase II Study of AZD4547 in Patients With Tumors Harboring Aberrations in the FGFR Pathway: Results From the NCI-MATCH Trial (EAY131) Subprotocol W.
Journal Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Vol
Issue
Date 2020 May 28
URL
Abstract Text 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.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.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%).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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
AZD4547 AZD-4547 FGFR1 Inhibitor 23 FGFR2 Inhibitor 16 FGFR3 Inhibitor 13 AZD4547 selectively binds and inhibits FGFR1, 2, and 3, which may result in the inhibition of FGFR-mediated signal transduction pathways and inhibition of tumor cell proliferation (PMID: 22369928, PMID: 30115694, PMID: 32463741).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 - TACC3 Advanced Solid Tumor sensitive AZD4547 Phase II Actionable In a Phase II (MATCH) trial, AZD4547 treatment resulted in partial response in 22% (2/9) and stable disease in 55% (5/9) of patients with advanced solid tumors harboring FGFR fusions, with a 6-month progression-free survival rate of 56%, including partial responses in 2 patients and stable disease for greater than 6 months in 1 of 8 patients harboring FGFR3-TACC3 (PMID: 32463741; NCT02465060). 32463741
FGFR2 amp Advanced Solid Tumor unknown AZD4547 Case Reports/Case Series Actionable In a Phase II (MATCH) trial, AZD4547 treatment resulted in stable disease in 2 of 3 of patients with advanced solid tumors harboring FGFR2 amplification, with a 6-month progression-free survival rate of 0% (PMID: 32463741; NCT02465060). 32463741
FGFR3 - TACC3 transitional cell carcinoma predicted - sensitive AZD4547 Case Reports/Case Series Actionable In a Phase II (MATCH) trial, AZD4547 treatment resulted in partial response in a patient with urothelial carcinoma harboring FGFR3-TACC3, with a 70% reduction in target lesions and a progression-free survival of 10.9 months (PMID: 32463741; NCT02465060). 32463741
FGFR3 act mut Advanced Solid Tumor predicted - sensitive AZD4547 Phase II Actionable In a Phase II (MATCH) trial, AZD4547 treatment resulted in an overall response rate of 10.5% (2/19) in patients with advanced solid tumors harboring FGFR2 or 3 activating single nucleotide variants and a 6-month progression-free survival rate of 6%, with a partial response in 1 and stable disease in 2 of 7 patients with FGFR3 activating mutations (PMID: 32463741; NCT02465060). 32463741
FGFR2 Y376C intrahepatic cholangiocarcinoma predicted - sensitive AZD4547 Case Reports/Case Series Actionable In a Phase II (MATCH) trial, AZD4547 treatment resulted in an overall response rate of 10.5% (2/19) in patients with advanced solid tumors harboring FGFR2 or 3 activating single nucleotide variants and a 6-month progression-free survival rate of 6%, including a partial response with 69% reduction in target lesion size and progression-free survival of 9.8 months in a patient with intrahepatic cholangiocarcinoma harboring FGFR2 Y376C (PMID: 32463741; NCT02465060). 32463741
FGFR2 act mut Advanced Solid Tumor predicted - sensitive AZD4547 Phase II Actionable In a Phase II (MATCH) trial, AZD4547 treatment resulted in an overall response rate of 10.5% (2/19) in patients with advanced solid tumors harboring FGFR2 or 3 activating single nucleotide variants and a 6-month progression-free survival rate of 6%, with a partial response in 1 and stable disease in 2 of 12 patients with FGFR2 activating mutations (PMID: 32463741; NCT02465060). 32463741
FGFR3 S249C renal pelvis transitional cell carcinoma predicted - sensitive AZD4547 Case Reports/Case Series Actionable In a Phase II (MATCH) trial, AZD4547 treatment resulted in an overall response rate of 10.5% (2/19) in patients with advanced solid tumors harboring FGFR2 or 3 activating single nucleotide variants and a 6-month progression-free survival rate of 6%, including stable disease for greater than 6 months in a patient with transitional cell carcinoma of the renal pelvis harboring FGFR2 S249C (PMID: 32463741; NCT02465060). 32463741
FGFR3 A391E bladder urothelial carcinoma predicted - sensitive AZD4547 Case Reports/Case Series Actionable In a Phase II (MATCH) trial, AZD4547 treatment resulted in an overall response rate of 10.5% (2/19) in patients with advanced solid tumors harboring FGFR2 or 3 single nucleotide variants and a 6-month progression-free survival (PFS) rate of 6%, with stable disease in 2 of 7 patients with FGFR3 activating mutations, and a partial response in a patient with urinary bladder transitional cell carcinoma harboring FGFR3 A391E (reported as A393E) (PMID: 32463741; NCT02465060). 32463741
FGFR3 - TACC3 cervical squamous cell carcinoma predicted - sensitive AZD4547 Case Reports/Case Series Actionable In a Phase II (MATCH) trial, AZD4547 treatment resulted in partial response in a patient with squamous cell carcinoma of the cervix harboring FGFR3-TACC3, with a 40% reduction in target lesion size and a progression-free survival of 4 months (PMID: 32463741; NCT02465060). 32463741
FGFR1 amp Advanced Solid Tumor unknown AZD4547 Phase II Actionable In a Phase II (MATCH) trial, AZD4547 treatment resulted in stable disease in 7 of 17 patients with advanced solid tumors harboring FGFR1 amplification, with 6 of the 17 patients experiencing progressive disease and 4 not evaluable for response, and a 6-month progression-free survival rate of 0% (PMID: 32463741; NCT02465060). 32463741