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

É. Van Cutsem (Lead / Corresponding author), Y-J Bang, W. Mansoor, R. D. Petty, Y. Chao, D. Cunningham, D. R. Ferry, N. R. Smith, P. Frewer, J. Rarnayake, P. K. Stockman, E. Kilgour, D. Landers

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    Abstract

    Background: Approximately 5–10% of gastric cancers (GCs) 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 off schedule of a 21-day cycle or intravenous paclitaxel 80 mg/m2 49 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 n = 41, paclitaxel n = 30), 67 received study treatment (AZD4547 n = 40, paclitaxel n = 27). Among all randomized patients, median PFS was 1.8 months with AZD4547 and 3.5 months with paclitaxel (one-sided p-value = 0.9581); 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.

    ClinicalTrials.gov identifier: 64 NCT01457846
    Original languageEnglish
    Pages (from-to)1316-1324
    Number of pages8
    JournalAnnals of Oncology
    Volume28
    Issue number6
    DOIs
    Publication statusPublished - 1 Jun 2017

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    Receptor, Fibroblast Growth Factor, Type 2
    Gene Amplification
    Paclitaxel
    Stomach
    Adenocarcinoma
    Safety
    Disease-Free Survival
    Therapeutics
    Biomarkers
    Stomach Neoplasms
    AZD4547
    Fluorescence In Situ Hybridization
    Heterografts
    Protein-Tyrosine Kinases
    Appointments and Schedules

    Keywords

    • AZD4547
    • Clincial Efficacy
    • Fibroblast Growth Factor Receptor
    • Gastric Cancer
    • Fluorescence in Situ Hybridization

    Cite this

    Van Cutsem, É. ; Bang, Y-J ; Mansoor, W. ; Petty, R. D. ; Chao, Y. ; Cunningham, D. ; Ferry, D. R. ; Smith, N. R. ; Frewer, P. ; Rarnayake, J. ; Stockman, P. K. ; Kilgour, E. ; Landers, D. / 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. In: Annals of Oncology. 2017 ; Vol. 28, No. 6. pp. 1316-1324.
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    title = "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",
    abstract = "Background: Approximately 5–10{\%} of gastric cancers (GCs) 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 off schedule of a 21-day cycle or intravenous paclitaxel 80 mg/m2 49 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 n = 41, paclitaxel n = 30), 67 received study treatment (AZD4547 n = 40, paclitaxel n = 27). Among all randomized patients, median PFS was 1.8 months with AZD4547 and 3.5 months with paclitaxel (one-sided p-value = 0.9581); 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.ClinicalTrials.gov identifier: 64 NCT01457846",
    keywords = "AZD4547, Clincial Efficacy, Fibroblast Growth Factor Receptor, Gastric Cancer, Fluorescence in Situ Hybridization",
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    Van Cutsem, É, Bang, Y-J, Mansoor, W, Petty, RD, Chao, Y, Cunningham, D, Ferry, DR, Smith, NR, Frewer, P, Rarnayake, J, Stockman, PK, Kilgour, E & Landers, D 2017, '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', Annals of Oncology, vol. 28, no. 6, pp. 1316-1324. https://doi.org/10.1093/annonc/mdx107

    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. / Van Cutsem, É. (Lead / Corresponding author); Bang, Y-J; Mansoor, W.; Petty, R. D.; Chao, Y.; Cunningham, D.; Ferry, D. R.; Smith, N. R.; Frewer, P.; Rarnayake, J.; Stockman, P. K.; Kilgour, E.; Landers, D.

    In: Annals of Oncology, Vol. 28, No. 6, 01.06.2017, p. 1316-1324.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - 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

    AU - Van Cutsem, É.

    AU - Bang, Y-J

    AU - Mansoor, W.

    AU - Petty, R. D.

    AU - Chao, Y.

    AU - Cunningham, D.

    AU - Ferry, D. R.

    AU - Smith, N. R.

    AU - Frewer, P.

    AU - Rarnayake, J.

    AU - Stockman, P. K.

    AU - Kilgour, E.

    AU - Landers, D.

    N1 - This work was supported by AstraZeneca. No grant numbers apply.

    PY - 2017/6/1

    Y1 - 2017/6/1

    N2 - Background: Approximately 5–10% of gastric cancers (GCs) 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 off schedule of a 21-day cycle or intravenous paclitaxel 80 mg/m2 49 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 n = 41, paclitaxel n = 30), 67 received study treatment (AZD4547 n = 40, paclitaxel n = 27). Among all randomized patients, median PFS was 1.8 months with AZD4547 and 3.5 months with paclitaxel (one-sided p-value = 0.9581); 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.ClinicalTrials.gov identifier: 64 NCT01457846

    AB - Background: Approximately 5–10% of gastric cancers (GCs) 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 off schedule of a 21-day cycle or intravenous paclitaxel 80 mg/m2 49 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 n = 41, paclitaxel n = 30), 67 received study treatment (AZD4547 n = 40, paclitaxel n = 27). Among all randomized patients, median PFS was 1.8 months with AZD4547 and 3.5 months with paclitaxel (one-sided p-value = 0.9581); 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.ClinicalTrials.gov identifier: 64 NCT01457846

    KW - AZD4547

    KW - Clincial Efficacy

    KW - Fibroblast Growth Factor Receptor

    KW - Gastric Cancer

    KW - Fluorescence in Situ Hybridization

    U2 - 10.1093/annonc/mdx107

    DO - 10.1093/annonc/mdx107

    M3 - Article

    VL - 28

    SP - 1316

    EP - 1324

    JO - Annals of Oncology

    JF - Annals of Oncology

    SN - 0923-7534

    IS - 6

    ER -