A phase 1b open label multicentre study of AZD4547 in patients with advanced squamous cell lung cancers.
Authors
Paik, PShen, R
Berger, M
Ferry, D
Soria, J
Mathewson, A
Rooney, C
Smith, N
Cullberg, M
Kilgour, Elaine
Landers, D
Frewer, P
Brooks, A
André, F
Affiliation
Medicine, Memorial Sloan-Kettering Cancer Center Department of Epidemiology and BiostatisticsIssue Date
2017-06-14
Metadata
Show full item recordAbstract
Squamous cell lung cancers (SQCLC) account for 25% of all NSCLCs, yet the prognosis of these patients is poor and treatment options are limited. Amplified FGFR1 is one of the most common oncogenic events in SQCLCs, occurring in ~20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with anti-tumor activity in FGFR1 amplified SQCLC cell lines and patient-derived xenografts. Experimental Design: Based on these data, we performed a phase 1 study of AZD4547 in patients with previously treated stage IV FGFR1 amplified SQCLCs (NCT00979134). FGFR1 amplification (FGFR1:CEP8 ≥ 2) was determined by FISH. The primary endpoint was safety/tolerability. Secondary endpoints included anti-tumor activity, pharmacokinetics, pharmacodynamics, and molecular analyses. Results: 15 FGFR1 amplified patients were treated. The most common related AEs were gastrointestinal and dermatologic. Grade ≥ 3 related AEs occurred in 3 patients (23%). Thirteen patients were evaluable for radiographic response assessment. The overall response rate was 8% (1 PR). 2/15 (13.3%) patients were progression free at 12 weeks and the median overall survival was 4.9 months. Molecular tests including next-generation sequencing, gene expression analysis, and FGFR1 immunohistochemistry showed poor correlation between gene amplification and expression, potential genomic modifiers of efficacy, and heterogeneity in the 8p11 amplicon. Conclusions:AZD4547 was tolerable at the 80mg po bid dose with modest anti-tumor activity. Detailed molecular studies show that these tumors are heterogeneous, with a range of mutational co-variates and stark differences in gene expression of the 8p11 amplicon that likely explain the modest efficacy of FGFR inhibition in this disease.Citation
A phase 1b open label multicentre study of AZD4547 in patients with advanced squamous cell lung cancers. 2017, Clin Cancer ResJournal
Clinical Cancer ResearchDOI
10.1158/1078-0432.CCR-17-0645PubMed ID
28615371Type
ArticleLanguage
enISSN
1078-0432ae974a485f413a2113503eed53cd6c53
10.1158/1078-0432.CCR-17-0645