Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial.
Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial.
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DOI：
10.1016/s1470-2045(13)70453-4
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发表时间：
2013-11
期刊：
影响因子：
--
通讯作者：
Demetri GD
中科院分区：
文献类型：
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作者：
Kang YK;Ryu MH;Yoo C;Ryoo BY;Kim HJ;Lee JJ;Nam BH;Ramaiya N;Jagannathan J;Demetri GD
我们进行了一项前瞻性、随机、双盲试验，以评估伊马替尼再激发治疗转移性和/或不可切除的胃肠道间质瘤（GIST）患者的疗效，这些患者在既往批准的酪氨酸激酶抑制剂（TKI）治疗后出现客观进展。2010年7月至2013年1月期间，81例既往从一线伊马替尼治疗中获益的患者（初始缓解或疾病稳定≥6个月）和随后至少接受伊马替尼和舒尼替尼治疗的进展，以1：1的比例随机分配（通过计算机生成的随机化列表和中央协调中心使用电话以双盲方式进行;随机区组排列方法，区组大小为2、4和6;按治疗线和体能状态分层）接受伊马替尼400 mg/天（n=41）或安慰剂（n=40）的最佳支持治疗。在研究者确定疾病进展时，允许交叉至开放标签伊马替尼。主要终点是通过盲法外部放射学审查确定的无进展生存期（PFS）。次要终点包括12周时的疾病控制率、总生存期和安全性。所有分析均基于全分析集。本研究注册于ClinicalTrials.gov，编号NCT 01151852。伊马替尼组的中位PFS为1.8个月（95%置信区间[CI]，1.7 - 3.6），而安慰剂组为0.9个月（95% CI，0.9 - 1.7）（进展或死亡的风险比，0.46; 95%置信区间[CI]，0.27 - 0.76; p= 0.005，双侧）。在安慰剂组中，37例患者（93%）在进展后交叉至开放标签伊马替尼治疗。伊马替尼恢复治疗后最常见的3级或以上不良事件是贫血（12/41，29%）、疲劳（4/41，10%）和高胆红素血症（3/41，7%）。尽管先前对伊马替尼耐药，但在至少伊马替尼和舒尼替尼治疗后疾病进展的GIST患者中，恢复伊马替尼显著改善了PFS，表明残留的大量疾病包含具有持续敏感性的克隆。
We conducted a prospective, randomised, double-blind trial to evaluate the efficacy of imatinib rechallenge in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) following objective progression of prior approved tyrosine kinase inhibitor (TKI) therapy. Between July 2010 and January 2013, 81 patients with prior benefit from first-line imatinib (initial response or stable disease for ≥6 months) and subsequent progression on at least imatinib and sunitinib were randomly assigned in a 1:1 ratio (by computer-generated randomisation list and the central coordinating center using telephone in a double-blind manner; randomised block permutation methods with block size of 2, 4, and 6; stratified by treatment line and performance status) to receive best supportive care with either imatinib 400 mg/day (n=41) or a placebo (n=40). At the time of disease progression, determined by the investigators, crossover to open-label imatinib was allowed. The primary endpoint was progression-free survival (PFS) determined by blinded external radiology review. Secondary endpoints included the disease control rate at 12 weeks, overall survival, and safety. All analyses were based on the full analysis set. This study is registered with ClinicalTrials.gov, number NCT01151852. The median PFS was 1·8 months (95% confidence interval [CI], 1·7–3·6) with imatinib as compared with 0·9 months (95% CI, 0·9–1·7) with placebo (hazard ratio for progression or death, 0·46; 95% confidence interval [CI], 0·27–0·76; p=0·005, two-sided). In the placebo arm, 37 patients (93%) crossed over to open-label imatinib after progression. The most common grade 3 or higher adverse events of imatinib resumption was anemia (12 of 41, 29%), fatigue (four of 41, 10%), and hyperbilirubinemia (three of 41, 7%). Despite prior resistance to imatinib, resumption of imatinib significantly improves PFS in GIST patients after disease progression on at least imatinib and sunitinib, demonstrating that residual bulk disease contains clones with continued sensitivity.