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A phase 1b open label multicentre study of AZD4547 in patients with advanced squamous cell lung cancers.
Paik, P Shen, R Berger, M Ferry, D Soria, J Mathewson, A Rooney, C Smith, N Cullberg, M Kilgour, Elaine
Paik, P
Shen, R
Berger, M
Ferry, D
Soria, J
Mathewson, A
Rooney, C
Smith, N
Cullberg, M
Kilgour, Elaine
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Abstract
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.
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2017-06-14
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A phase 1b open label multicentre study of AZD4547 in patients with advanced squamous cell lung cancers. 2017, Clin Cancer Res