A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers

Abstract

<b>Purpose:</b> 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 <i>FGFR1</i> is one of the most common oncogenic events in SQCLCs, occurring in approximately 20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with antitumor activity in <i>FGFR1</i>-amplified SQCLC cell lines and patient-derived xenografts.<b>Experimental Design:</b> On the basis of these data, we performed a phase I study of AZD4547 in patients with previously treated stage IV <i>FGFR1</i>-amplified SQCLCs (NCT00979134). <i>FGFR1</i> amplification (FGFR1:CEP8 ≥ 2) was determined by FISH. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, pharmacodynamics, and molecular analyses.<b>Results:</b> Fifteen <i>FGFR1</i>-amplified patients were treated. The most common related adverse events (AE) 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). Two of 15 patients (13.3%) 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 8p11 amplicon.<b>Conclusions:</b> AZD4547 was tolerable at a dosage of 80 mg oral twice a day, with modest antitumor activity. Detailed molecular studies show that these tumors are heterogeneous, with a range of mutational covariates and stark differences in gene expression of the 8p11 amplicon that likely explain the modest efficacy of FGFR inhibition in this disease. <i>Clin Cancer Res; 23(18); 5366-73. ©2017 AACR</i>.