A phase II, randomised study of mFOLFOX6 with or without the Akt inhibitor ipatasertib in patients with locally advanced or metastatic gastric or gastroesophageal junction cancer
A phase II, randomised study of mFOLFOX6 with or without the Akt inhibitor ipatasertib in patients with locally advanced or metastatic gastric or gastroesophageal junction cancer
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DOI：
10.1016/j.ejca.2018.11.017
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发表时间：
2019-02-01
影响因子：
8.4
通讯作者：
Ajani, J. A.
中科院分区：
文献类型：
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作者：
Bang, Y-J;Kang, Y-K;Ajani, J. A.
背景：Akt 激活在胃/胃食管交界癌 (GC/GEJC) 中很常见，并且与化疗耐药相关。使用泛 Akt 抑制剂 ipatasertib 治疗可能会增强 GC/GEJC 化疗的疗效。 患者和方法：在这项随机、双盲、安慰剂对照、多中心 II 期试验中，不适合根治性治疗的局部晚期或转移性 GC/GEJC 患者按 1:1 随机分配接受 ipatasertib 或安慰剂，加 mFOLFOX6（改良方案亚叶酸、推注和输注 5-氟尿嘧啶 [5-FU] 和奥沙利铂）。共同主要终点是意向治疗（ITT）人群以及磷酸酶和张力蛋白同源物（PTEN）低的患者的无进展生存期（PFS）。次要终点包括 PI3K/Akt 通路激活肿瘤患者的 PFS； ITT 人群的总体生存率、研究者评估的客观缓解率和缓解持续时间；结果：在 153 名入组患者中，ipatasertib/mFOLFOX6 组的中位 PFS (ITT) 为 6.6 个月（90% 置信区间 [CI]，5.7-7.5），而安慰剂/mFOLFOX6 组的中位 PFS (ITT) 为 7.5 个月（90% CI，6.2-8.1）（风险比，1.12；90% CI， 0.81-1.55；P = 0.56）。与安慰剂/mFOLFOX6 相比，在生物标志物选择的患者亚组（PTEN 低和 PI3K/Akt 通路激活的肿瘤）中，使用 ipatasertib/mFOLFOX6 与安慰剂/mFOLFOX6 相比，没有观察到统计学上显着的 PFS 获益。其他次要终点不支持 ipatasertib/mFOLFOX6 治疗组。各组间出现≥ 1 种不良事件（AE，100% 与 98%）和≥ 3 级 AE（79% 与 74%）的患者比例相似。 ipatasertib 组报告的导致治疗退出的 AE 发生率较高（16% 对 6%），而严重 AE 发生率较高（54% 对 43%）。 ipatasertib 组和安慰剂组分别发生 39 例和 29 例死亡。结论：与安慰剂/mFOLFOX6 相比，ipatasertib/mFOLFOX6 并未改善未选择或生物标志物选择患者的 PFS。没有观察到意外的安全问题。试验注册：ClinicalTrials.gov (NCT01896531)。 (C) 2018 Elsevier Ltd. 保留所有权利。
Background: Akt activation is common in gastric/gastroesophageal junction cancer (GC/GEJC) and is associated with chemotherapy resistance. Treatment with ipatasertib, a pan-Akt inhibitor, may potentiate the efficacy of chemotherapy in GC/GEJC.Patients and methods: In this randomised, double-blind, placebo-controlled, multicentre, phase II trial, patients with locally advanced or metastatic GC/GEJC not amenable to curative therapy were randomised 1:1 to receive ipatasertib or placebo, plus mFOLFOX6 (modified regimen of leucovorin, bolus and infusional 5-fluorouracil [5-FU], and oxaliplatin). The co-primary end-point was progression-free survival (PFS) in the intent-to-treat (ITT) population and in phosphatase and tensin homolog (PTEN)-low patients. Secondary end-points included PFS in patients with PI3K/Akt pathway-activated tumours; overall survival, investigator-assessed objective response rate and duration of response in the ITT population; and safety assessments.Results: In 153 enrolled patients, the median PFS (ITT) was 6.6 months (90% confidence interval [CI], 5.7-7.5) with ipatasertib/mFOLFOX6 versus 7.5 months (90% CI, 6.2-8.1) with placebo/mFOLFOX6 (hazard ratio, 1.12; 90% CI, 0.81-1.55; P = 0.56). No statistically significant PFS benefit was observed in biomarker-selected patient subgroups (PTEN-low and PI3K/Akt pathway-activated tumours) with ipatasertib/mFOLFOX6 versus placebo/mFOLFOX6. Other secondary end-points did not favour the ipatasertib/mFOLFOX6 treatment arm. The percentages of patients with >= 1 adverse event (AE, 100% versus 98%) and grade >= 3 AEs (79% versus 74%) were similar between arms. Higher rates of AEs leading to treatment withdrawal (16% versus 6%) and serious AEs were reported in the ipatasertib arm (54% versus 43%). Thirty-nine and 29 deaths occurred in the ipatasertib and placebo arms, respectively.Conclusions: Ipatasertib/mFOLFOX6 compared with placebo/mFOLFOX6 did not improve PFS in unselected or biomarker-selected patients. No unexpected safety concerns were observed. Trial registration: ClinicalTrials.gov (NCT01896531). (C) 2018 Elsevier Ltd. All rights reserved.