A phase 1b open label multicentre study of AZD4547 in patients with advanced squamous cell lung cancers.
AffiliationMedicine, Memorial Sloan-Kettering Cancer Center Department of Epidemiology and Biostatistics
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AbstractSquamous 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.
CitationA phase 1b open label multicentre study of AZD4547 in patients with advanced squamous cell lung cancers. 2017, Clin Cancer Res
JournalClinical Cancer Research