Phosphatidylinositol 3-Kinase Inhibition by Copanlisib in Relapsed or Refractory Indolent Lymphoma
Phosphatidylinositol 3-Kinase Inhibition by Copanlisib in Relapsed or Refractory Indolent Lymphoma
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DOI：
10.1200/jco.2017.75.4648
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发表时间：
2017-12-10
影响因子：
45.3
通讯作者：
Zinzani, Pier Luigi
中科院分区：
文献类型：
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作者：
Dreyling, Martin;Santoro, Armando;Zinzani, Pier Luigi
目的磷脂酰肌醇3-激酶（PI 3 K）信号通路对恶性B细胞的增殖和存活至关重要。Copanlisib是一种对PI 3 K和PI 3 K亚型具有主要活性的泛I类PI 3 K抑制剂，已在惰性淋巴瘤患者中证明了疗效和可管理的安全性。和28天周期中的15天。主要终点为客观缓解率;次要终点包括缓解持续时间、无进展生存期和总生存期。此外，安全性和基因表达进行了evaluated.ResultsMedian年龄为63岁（范围，25至82岁），和患者接受了中位数的三个（范围，2至9）前方案。客观缓解率为59%（142例患者中的84例）; 12%的患者达到完全缓解。中位缓解时间为53天。中位缓解持续时间为22.6个月，中位无进展生存期为11.2个月，中位总生存期尚未达到。最常见的治疗后出现的不良事件为一过性高血糖（所有等级，50%; 3级或4级，41%）和一过性高血压（所有等级，30%; 3级，24%）。其他3级事件包括中性粒细胞计数降低（24%）和肺部感染（15%）。copanlisib的高应答率与PI 3 K/B细胞受体信号通路基因的高表达相关。结论copanlisib抑制PI 3 K/B细胞受体信号通路基因表达对复发性或难治性惰性淋巴瘤患者具有显著的疗效和可管理的安全性。
PurposePhosphatidylinositol 3-kinase (PI3K) signaling is critical for the proliferation and survival of malignant B cells. Copanlisib, a pan-class I PI3K inhibitor with predominant activity against PI3K- and - isoforms, has demonstrated efficacy and a manageable safety profile in patients with indolent lymphoma.Patients and MethodsIn this phase II study, 142 patients with relapsed or refractory indolent lymphoma after two or more lines of therapy were enrolled to receive copanlisib 60 mg intravenously on days 1, 8, and 15 of a 28-day cycle. The primary end point was objective response rate; secondary end points included duration of response, progression-free survival, and overall survival. In addition, safety and gene expression were evaluated.ResultsMedian age was 63 years (range, 25 to 82 years), and patients had received a median of three (range, two to nine) prior regimens. The objective response rate was 59% (84 of 142 patients); 12% of patients achieved a complete response. Median time to response was 53 days. Median duration of response was 22.6 months, median progression-free survival was 11.2 months, and median overall survival had not yet been reached. The most frequent treatment-emergent adverse events were transient hyperglycemia (all grades, 50%; grade 3 or 4, 41%) and transient hypertension (all grades, 30%; grade 3, 24%). Other grade 3 events included decreased neutrophil count (24%) and lung infection (15%). High response rates to copanlisib were associated with high expression of PI3K/B-cell receptor signaling pathway genes.ConclusionPI3K- and - inhibition by copanlisib demonstrated significant efficacy and a manageable safety profile in heavily pretreated patients with relapsed or refractory indolent lymphoma.