Activity of IPI-504, a Novel Heat-Shock Protein 90 Inhibitor, in Patients With Molecularly Defined Non-Small-Cell Lung Cancer
Activity of IPI-504, a Novel Heat-Shock Protein 90 Inhibitor, in Patients With Molecularly Defined Non-Small-Cell Lung Cancer
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DOI：
10.1200/jco.2010.30.8338
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发表时间：
2010-11-20
影响因子：
45.3
通讯作者：
Natale, Ronald
中科院分区：
文献类型：
--
作者：
Sequist, Lecia V.;Gettinger, Scott;Natale, Ronald
目的 IPI-504 是一种新型、水溶性、有效的热休克蛋白 90 (Hsp90) 抑制剂。其潜在的抗癌活性已在临床前体外和体内模型中得到验证。我们研究了晚期、分子定义的非小细胞肺癌 (NSCLC) 患者接受表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI) 治疗后 IPI-504 的活性。 患者和方法 既往接受过 EGFR TKI 治疗且肿瘤组织可用于分子基因分型的晚期 NSCLC 患者被纳入这项 IPI-504 单药治疗的前瞻性、非随机、多中心 II 期研究。主要结局是客观缓解率（ORR）。次要目标包括安全性、无进展生存期 (PFS) 以及分子亚型的活性分析。结果 2007 年 12 月至 2009 年 5 月期间，来自 10 个美国癌症中心的 76 名患者入组。在整个研究人群中观察到的 ORR 为 7%（76 人中的 5 人），EGFR 野生型患者的 ORR 为 10%（40 人中的 4 人），EGFR 突变患者的 ORR 为 4%（28 人中的 1 人）。尽管两个 EGFR 组均低于 20% 的目标 ORR，但在三名 ALK 基因重排患者中，两名患者出现部分缓解，第三名患者疾病长期稳定（7.2 个月，肿瘤大小缩小 24%）。最常见的不良事件包括 1 级和 2 级疲劳、恶心和腹泻。 9 名患者 (11.8%) 观察到 3 级或以上肝功能异常。 结论 IPI-504 在 NSCLC 患者中具有临床活性，特别是在 ALK 重排患者中。 J 临床肿瘤学杂志 28：4953-4960。 (c) 2010 年美国临床肿瘤学会
Purpose IPI-504 is a novel, water-soluble, potent inhibitor of heat-shock protein 90 (Hsp90). Its potential anticancer activity has been validated in preclinical in vitro and in vivo models. We studied the activity of IPI-504 after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in patients with advanced, molecularly defined non-small-cell lung cancer (NSCLC).Patients and Methods Patients with advanced NSCLC, prior treatment with EGFR TKIs, and tumor tissue available for molecular genotyping were enrolled in this prospective, nonrandomized, multicenter, phase II study of IPI-504 monotherapy. The primary outcome was objective response rate (ORR). Secondary aims included safety, progression-free survival (PFS), and analysis of activity by molecular subtypes.Results Seventy-six patients were enrolled between December 2007 and May 2009 from 10 United States cancer centers. An ORR of 7% (five of 76) was observed in the overall study population, 10% (four of 40) in patients who were EGFR wild-type, and 4% (one of 28) in those with EGFR mutations. Although both EGFR groups were below the target ORR of 20%, among the three patients with an ALK gene rearrangement, two had partial responses and the third had prolonged stable disease (7.2 months, 24% reduction in tumor size). The most common adverse events included grades 1 and 2 fatigue, nausea, and diarrhea. Grade 3 or higher liver function abnormalities were observed in nine patients (11.8%).Conclusion IPI-504 has clinical activity in patients with NSCLC, particularly among patients with ALK rearrangements. J Clin Oncol 28:4953-4960. (c) 2010 by American Society of Clinical Oncology