Pimitespib in patients with advanced gastrointestinal stromal tumor (CHAPTER-GIST-301): a randomized, double-blind, placebo-controlled phase III trial
Pimitespib in patients with advanced gastrointestinal stromal tumor (CHAPTER-GIST-301): a randomized, double-blind, placebo-controlled phase III trial
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DOI：
10.1016/j.annonc.2022.05.518
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发表时间：
2022-09-05
影响因子：
50.5
通讯作者：
Doi, T.
中科院分区：
文献类型：
--
作者：
Kurokawa, Y.;Honma, Y.;Doi, T.
背景：对酪氨酸激酶抑制剂（TKIs）难治的晚期胃肠道间质瘤（GIST）预后较差。这项随机、安慰剂对照的III期试验评估了吡咪司匹布（一种新型热休克蛋白90抑制剂）在标准TKIs难治性晚期GIST中的疗效和安全性。患者和方法：组织学证实的GIST对伊马替尼、舒尼替尼和瑞非尼难治的患者随机分为两组：口服吡咪替布160 mg/天或安慰剂，每周连续5天，21天为一个周期。通过盲法中心放射学检查（BCRR），疾病进展后，允许交叉使用开放标签的吡咪司匹。主要终点是全分析集BCRR的无进展生存期（PFS）。次要终点包括使用保秩结构失效时间（RPSFT）方法调整的总生存期（OS），以减少交叉的预期混杂影响。结果：从2018年10月31日到2020年4月30日，86名患者被随机分配到吡咪司匹（n = 58）或安慰剂（n = 28）组。吡咪替布组的中位PFS为2.8个月[95%可信区间（CI） 1.6-2.9个月]，安慰剂组为1.4个月（0.9-1.8个月）[风险比（HR） 0.51 (95% CI 0.30-0.87)；单侧P = 0.006]。与安慰剂相比，吡咪司匹可改善交叉过度调整OS [HR 0.42(0.21-0.85)，单侧P 1/4 0.007]。17例（60.7%）接受安慰剂的患者转为吡咪司匹；交叉后的中位PFS为2.7个月（95% CI 0.7-4.1个月）。最常见的治疗相关不良事件（ae）（>= 30%）是腹泻（74.1%）和食欲下降（31.0%）；最常见的(>= 10%)>= 3级治疗相关AE为腹泻（13.8%）。3例（5.2%）患者发生与治疗相关的不良事件导致吡咪替匹停药。结论：与安慰剂相比，Pimitespib显著改善了PFS和交叉过度调整OS，并且在标准TKIs难治性晚期GIST患者中具有可接受的安全性。
Background: Prognosis of advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) is poor. This randomized, placebo-controlled, phase III trial evaluated the efficacy and safety of pimitespib, a novel heat shock protein 90 inhibitor, in advanced GIST refractory to standard TKIs.Patients and methods: Patients with histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib were randomized 2 : 1 to oral pimitespib 160 mg/day or placebo for 5 consecutive days per week in 21-day cycles. Following disease progression by blinded central radiological review (BCRR), cross-over to open-label pimitespib was permitted. The primary endpoint was progression-free survival (PFS) by BCRR in the full analysis set. Secondary endpoints included overall survival (OS) adjusted using the rank-preserving structural failure time (RPSFT) method to reduce the expected confounding impact of cross-over.Results: From 31 October 2018 to 30 April 2020, 86 patients were randomized to pimitespib (n = 58) or placebo (n = 28). Median PFS was 2.8 months [95% confidence interval (CI) 1.6-2.9 months] with pimitespib versus 1.4 months (0.9-1.8 months) with placebo [hazard ratio (HR) 0.51 (95% CI 0.30-0.87); one-sided P = 0.006]. Pimitespib showed an improvement in cross-over-adjusted OS compared with placebo [HR 0.42 (0.21-0.85), one-sided P 1/4 0.007]. Seventeen (60.7%) patients receiving placebo crossed-over to pimitespib; median PFS after cross-over was 2.7 months (95% CI 0.7-4.1 months). The most common (>= 30%) treatment-related adverse events (AEs) with pimitespib were diarrhea (74.1%) and decreased appetite (31.0%); the most common (>= 10%) grade >= 3 treatment-related AE was diarrhea (13.8%). Treatment-related AEs leading to pimitespib discontinuation occurred in three (5.2%) patients.Conclusions: Pimitespib significantly improved PFS and cross-over-adjusted OS compared with placebo and had an acceptable safety profile in patients with advanced GIST refractory to standard TKIs.