A phase Ib open-label multicenter study of AZD4547 in patients with advanced squamous cell lung cancers Journal Article

Authors: Paik, P. K.; Shen, R.; Berger, M. F.; Ferry, D.; Soria, J. C.; Mathewson, A.; Rooney, C.; Smith, N. R.; Cullberg, M.; Kilgour, E.; Landers, D.; Frewer, P.; Brooks, N.; André, F.
Article Title: A phase Ib open-label multicenter study of AZD4547 in patients with advanced squamous cell lung cancers
Abstract: Purpose: 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 approximately 20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with antitumor activity in FGFR1-amplified SQCLC cell lines and patient-derived xenografts. Experimental Design: On the basis of these data, we performed a phase I 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 antitumor activity, pharmacokinetics, pharmacodynamics, and molecular analyses. Results: Fifteen FGFR1-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. Conclusions: 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. ©2017 AACR.
Journal Title: Clinical Cancer Research
Volume: 23
Issue: 18
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2017-09-15
Start Page: 5366
End Page: 5373
Language: English
DOI: 10.1158/1078-0432.ccr-17-0645
PROVIDER: scopus
PMCID: PMC5600836
PUBMED: 28615371
Notes: Article -- Export Date: 2 October 2017 -- Source: Scopus
Citation Impact
MSK Authors
  1. Ronglai Shen
    157 Shen
  2. Paul K Paik
    149 Paik
  3. Michael Forman Berger
    569 Berger