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.
Ann Oncol. 2022 Sep;33(9):959-967. doi: 10.1016/j.annonc.2022.05.518. Epub 2022 Jun 8.
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 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.
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.
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.
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。
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。
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%）。
与安慰剂相比，pimitespib 显著改善了 PFS 和交叉调整后的 OS，且在标准 TKI 耐药的晚期 GIST 患者中具有可接受的安全性。
