吡咯烷二硫代氨基甲酸酯（Pimitespib）治疗晚期胃肠道间质瘤（CHAPTER-GIST-301）患者的随机、双盲、安慰剂对照 III 期临床试验。

Pimitespib in patients with advanced gastrointestinal stromal tumor (CHAPTER-GIST-301): a randomized, double-blind, placebo-controlled phase III trial.

机构信息

Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.

出版信息

Ann Oncol. 2022 Sep;33(9):959-967. doi: 10.1016/j.annonc.2022.05.518. Epub 2022 Jun 8.

DOI:10.1016/j.annonc.2022.05.518

PMID:35688358

Abstract

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 = 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.

摘要

背景

对酪氨酸激酶抑制剂（TKI）耐药的晚期胃肠道间质瘤（GIST）患者预后较差。这项随机、安慰剂对照、III 期试验评估了新型热休克蛋白 90 抑制剂 pimitespib 在标准 TKI 耐药的晚期 GIST 患者中的疗效和安全性。

患者和方法

组织学证实的对伊马替尼、舒尼替尼和regorafenib 耐药的 GIST 患者按 2:1 随机分配，接受每日口服 pimitespib 160mg/天或安慰剂，每周连续 5 天，每 21 天为一个周期。经盲法中心放射学审查（BCRR）确认疾病进展后，允许交叉至开放标签 pimitespib。主要终点是 BCRR 评估的全分析集无进展生存期（PFS）。次要终点包括使用秩保持结构失效时间（RPSFT）方法调整的总生存期（OS），以降低交叉预期的混杂影响。

结果

2018 年 10 月 31 日至 2020 年 4 月 30 日，86 名患者被随机分配至 pimitespib（n=58）或安慰剂（n=28）组。pimitespib 组的中位 PFS 为 2.8 个月[95%置信区间（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，pimitespib 组在交叉调整后的 OS 方面有改善[HR 0.42（0.21-0.85），单侧 P=0.007]。17 名（60.7%）接受安慰剂的患者交叉至 pimitespib 组；交叉后中位 PFS 为 2.7 个月[95%CI 0.7-4.1 个月]。与 pimitespib 相关的最常见（≥30%）治疗相关不良事件（AE）为腹泻（74.1%）和食欲下降（31.0%）；最常见（≥10%）的 3 级治疗相关 AE 为腹泻（13.8%）。因治疗相关 AEs 而导致 pimitespib 停药的患者有 3 名（5.2%）。