A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors ( GIST) following failure of at least imatinib and sunitinib
A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors ( GIST) following failure of at least imatinib and sunitinib
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DOI：
10.1093/annonc/mdt484
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发表时间：
2014-01-01
影响因子：
50.5
通讯作者：
George, S.
中科院分区：
文献类型：
--
作者：
Ganjoo, K. N.;Villalobos, V. M.;George, S.
背景：晚期gist是无法治愈的，但通常使用酪氨酸激酶抑制剂（TKIs）治疗数年。大多数gist在KIT或PDGFRA中存在致癌激活突变。对许多患者来说，TKIs抑制这种激活突变最常导致持久的疾病控制。然而，几乎所有患者对这些tki产生耐药性，通常是由于继发性突变的发展，这预示着需要新的治疗选择。我们进行了一项II期研究，评估pazopanib，广谱TKI抑制KIT， vegfr（-1， -2和-3）和PDGFR （- α和β）在至少伊马替尼和舒尼替尼失败后晚期GIST患者的疗效和毒性。方法：患者口服帕唑帕尼800 mg，每日1次。每8周（2个周期）通过CT扫描评估所有患者的疗效。患者继续服用帕唑帕尼，直到病情进展或出现不可接受的毒性。主要终点是根据RECIST 1.1的24周无进展[完全缓解+部分缓解+疾病稳定（SD）]率（NPR）。次要终点包括PFS、OS和毒性。结果：2011年8月至2012年9月，共有25例患者在两家机构接受治疗。先前治疗的中位数为3（范围2-7）。pazopanib共使用90个周期，每位患者中位数为2个周期（范围1至17+）。12例（48%）患者在任何时间观察到SD的最佳反应。NPR为17%[95%置信区间（CI） 4.5-37]。除1例患者外，所有患者因PD （n = 19）或不耐受（n = 4）而中断治疗。一名琥珀酸脱氢酶（SDH）缺乏的GIST患者在17个周期后表现出持续的疾病控制。整个队列的中位PFS为1.9个月（95% CI 1.6-5.2），中位OS为10.7个月（95% CI 3.9-NR）。结论：帕唑帕尼耐受性相当好，没有意外的毒性。Pazopanib作为单一药物在未选择的重度预处理的晚期GIST患者中具有边际活性。
Background: Advanced GISTs are incurable, but often treatable for years with tyrosine kinase inhibitors (TKIs). The majority of GISTs harbor an oncogenic activating mutation in KIT or PDGFRA. Inhibition of this activating mutation with TKIs most often leads to durable disease control for many patients. However, almost all patients develop resistance to these TKIs, typically due to the development of secondary mutations, heralding the need for new therapeutic options. We conducted a phase II study evaluating the efficacy and toxicity of pazopanib, a broad spectrum TKI inhibiting KIT, VEGFRs (-1, -2, and -3), and PDGFR (-alpha and-beta) in patients with advanced GIST following failure of at least imatinib and sunitinib.Methods: Patients received pazopanib 800 mg orally once daily. All patients were assessed for efficacy with CT scans every 8 weeks (two cycles). Patients continued pazopanib until progression or unacceptable toxicity. The primary end point was the 24-week nonprogression [complete response+partial response+stable disease (SD)] rate (NPR) per RECIST 1.1. Secondary end points included PFS, OS, and toxicity.Results: Between August 2011 and September 2012, a total of 25 patients were treated at two institutions. Median number of prior therapy was 3 (range 2-7). A total of 90 cycles of pazopanib were administered, with a median of two cycles (range 1 to 17+) per patient. Best response of SD at any time was observed in 12 (48%) patients. The NPR was 17% [95% confidence interval (CI) 4.5-37]. All but one patient discontinued protocol either due to PD (n = 19) or intolerance (n = 4). One patient with succinate dehydrogenase (SDH)-deficient GIST exhibited continuing disease control after 17 cycles. The median PFS for the entire cohort was 1.9 months (95% CI 1.6-5.2), and the median OS was 10.7 months (95% CI 3.9-NR).Conclusions: Pazopanib was reasonably well tolerated with no unexpected toxicities. Pazopanib as a single agent has marginal activity in unselected heavily pretreated patients with advanced GIST.