A randomized, open-label study of the efficacy and safety of AZD4547 monotherapy versus paclitaxel for the treatment of advanced gastric adenocarcinoma with FGFR2 polysomy or gene amplification

E. Van Cutsem, Y. J. Bang, W. Mansoor, R. D. Petty, Y. Chao, D. Cunningham, D. R. Ferry, N. R. Smith, P. Frewer, J. Ratnayake, P. K. Stockman, D. Landers, E. Kilgour

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Approximately 5%-10% of gastric cancers have a fibroblast growth factor receptor-2 (FGFR2) gene amplification. AZD4547 is a selective FGFR-1, 2, 3 tyrosine kinase inhibitor with potent preclinical activity in FGFR2 amplified gastric adenocarcinoma SNU16 and SGC083 xenograft models. The randomized phase II SHINE study (NCT01457846) investigated whether AZD4547 improves clinical outcome versus paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma displaying FGFR2 polysomy or gene amplification detected by fluorescence in situ hybridization. Patients and methods: Patients were randomized 3:2 (FGFR2 gene amplification) or 1:1 (FGFR2 polysomy) to AZD4547 or paclitaxel. Patients received AZD4547 80 mg twice daily, orally, on a 2 weeks on/1 week offschedule of a 21-day cycle or intravenous paclitaxel 80 mg/m2 administered weekly on days 1, 8, and 15 of a 28-day cycle. The primary end point was progression-free survival (PFS). Safety outcomes were assessed and an exploratory biomarker analysis was undertaken. Results: Of 71 patients randomized (AZD4547 n1/441, paclitaxel n1/430), 67 received study treatment (AZD4547 n1/440, paclitaxel n1/427). Among all randomized patients, median PFS was 1.8 months with AZD4547 and 3.5 months with paclitaxel (one-sided P1/40.9581); median follow-up duration for PFS was 1.77 and 2.12 months, respectively. The incidence of adverse events was similar in both treatment arms. Exploratory biomarker analyses revealed marked intratumor heterogeneity of FGFR2 amplification and poor concordance between amplification/polysomy and FGFR2 mRNA expression. Conclusions: AZD4547 did not significantly improve PFS versus paclitaxel in gastric cancer FGFR2 amplification/polysomy patients. Considerable intratumor heterogeneity for FGFR2 gene amplification and poor concordance between FGFR2 amplification/polysomy and FGFR2 expression indicates the need for alternative predictive biomarker testing. AZD4547 was generally well tolerated.

Original languageEnglish
Article numbermdx107
Pages (from-to)1316-1324
Number of pages9
JournalAnnals of Oncology
Volume28
Issue number6
DOIs
Publication statusPublished - 1 Jun 2017

Keywords

  • AZD4547
  • Clinical efficacy
  • Fibroblast growth factor receptor
  • Fluorescence in situ hybridization
  • Gastric cancer

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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