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Exploratory biomarker analysis of a phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), in patients with advanced solid tumors.
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2014
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PathologyAdvanced Solid TumorsCancer BiologyTumor BiologyExploratory Biomarker AnalysisOncologyGenitourinary CancerCancer Cell BiologyFgfr 1Fibroblast Growth FactorRadiation OncologyFgfr Gene AmplificationMolecular OncologyCancer ResearchCancer TreatmentCancer GeneticsCell BiologyLung CancerUrologyHigh Fgfr AmplificationCancer GenomicsMedicine
11010 Background: AZD4547 is a selective inhibitor of FGFR 1, 2, and 3, with activity in patient-derived explant models with FGFR gene amplification. Study 1C1 assessed safety and clinical activity of AZD4547 (80 mg bid continuous dosing), in patients with advanced solid tumors, prospectively selected for amplification of FGFR 1 or 2. FGFR gene amplification status was determined using fluorescent in situ hybridization (FISH) analysis of archival tumor tissue. Methods: Analysis of FFPE diagnostic tumor samples included FGFR expression by IHC, expression analysis of ~200 pathway related genes by Nanostring and targeted Next Generation Sequencing (NGS) of a 287 gene panel at Foundation Medicine. Results: Of 21 patients dosed with AZD4547, seven had high FGFR amplification (ratio FGFR:Centromeric probe ≥ 3.0) and three of these, a squamous NSCLC, breast and bladder cancer patients, had target lesion shrinkage or prolonged (≥24 weeks) disease stabilization. NGS analysis of tumor from a partial response squamous NSCLC patient, confirmed high FGFR1 amplification together with amplification of 11q13 genes FGF3/4/19 and CCND1. A breast cancer patient, with 25% reduction in target lesions, was highly FGFR1 amplified by NGS and expressed FGFR1 protein. Four patients with high FGFR gene amplification by FISH had little sign of efficacy. Of these, one patient was not confirmed FGFR amplified by NGS analysis, likely due to tumor heterogeneity. The other three patient tumors had an additional Receptor Tyrosine Kinase (RTK) amplification (IGF1R, HER2 or EGFR), with accompanying high expression. Two out of three bladder cancer patients experienced prolonged disease stabilization, both with marked FGFR1 and FGFR3 expression, one with high FGFR1amplification while an FGFR3 ligand binding domain mutation was found in tumor from the other. Conclusions: In this AZD4547 Phase I study, evidence of FGFR pathway expression was observed in tumor samples from advanced cancer patients with signs of efficacy. Co-amplification of RTKs may confer resistance to AZD4547. FGFR1/3 expression, amplification and mutation are potential selection markers for bladder cancer patients. Clinical trial information: NCT00979134.