Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology			2020 May 28	2407-2417	J Clin Oncol

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
AZD4547	AZD4547	147	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AZD4547		AZD-4547	FGFR1 Inhibitor 28 FGFR2 Inhibitor 23 FGFR3 Inhibitor 19	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), and has demonstrated inhibitory effects on NTRK signaling (PMID: 34790577).

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 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 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
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
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 FGFR3 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
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