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
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
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DOI：
10.1093/annonc/mdx107
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发表时间：
2017-06-01
影响因子：
50.5
通讯作者：
Landers, D.
中科院分区：
文献类型：
--
作者：
Van Cutsem, E.;Bang, Y. -J.;Landers, D.
背景：大约5%-10%的胃癌存在成纤维细胞生长因子受体2（FGFR 2）基因扩增。AZD 4547是一种选择性FGFR-1，2，3酪氨酸激酶抑制剂，在FGFR 2扩增的胃腺癌SNU 16和SGC 083异种移植模型中具有有效的临床前活性。随机II期SHINE研究（NCT 01457846）研究了AZD 4547与紫杉醇相比作为二线治疗是否改善了荧光原位杂交检测到FGFR 2多体性或基因扩增的晚期胃腺癌患者的临床结局。（FGFR 2基因扩增）或1：1（FGFR 2多体性）与AZD 4547或紫杉醇。患者接受AZD 4547 80 mg每日2次口服，2周给药/1周停药，21天为一个周期，或紫杉醇80 mg/m2静脉给药，每周一次，第1、8和15天，28天为一个周期。主要终点是无进展生存期（PFS）。结果：在71例随机分组的患者中（AZD 4547 n = 41，紫杉醇n = 30），67例接受研究治疗（AZD 4547 n = 40，紫杉醇n = 27）。在所有随机化患者中，AZD 4547组的中位PFS为1.8个月，紫杉醇组为3.5个月（单侧P = 0.9581）; PFS的中位随访时间分别为1.77和2.12个月。两个治疗组的不良事件发生率相似。探索性生物标志物分析显示FGFR 2扩增的显著瘤内异质性和扩增/多体性与FGFR 2 mRNA表达之间的一致性较差。结论：在胃癌FGFR 2扩增/多体性患者中，与紫杉醇相比，AZD 4547未显著改善PFS。FGFR 2基因扩增的相当大的肿瘤内异质性以及FGFR 2扩增/多体性与FGFR 2表达之间的不一致性表明需要替代预测性生物标志物检测。AZD 4547通常耐受性良好。
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 off schedule of a 21-day cycle or intravenous paclitaxel 80 mg/m(2) 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 = 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.