Martin Dreyling, Ludwig Maximilians University of Munich, Munich; Georg Lenz, University Hospital Münster, Münster; Marius Giurescu, Karl Köchert, Henrik Seidel, and Florian Hiemeyer, Bayer AG, Berlin, Germany; Armando Santoro, Humanitas Clinical and Research Center, Rozzano; Pier Luigi Zinzani, University of Bologna, Bologna, Italy; Luigina Mollica, Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; George A. Follows, Addenbrooke's Hospital, Cambridge, United Kingdom; Won Seog Kim, Samsung Medical Center, Seoul, South Korea; Arnon Nagler, Tel Aviv University, Tel HaShomer, Israel; Panayiotis Panayiotidis, National and Kapodistrian University of Athens, Athens, Greece; Judit Demeter, Semmelweis University, Budapest, Hungary; Muhit Özcan, Ankara University School of Medicine, Ankara, Turkey; Marina Kosinova, Kemerovo Regional Clinical Hospital, Kemerovo, Russian Federation; Krimo Bouabdallah, University Hospital of Bordeaux, Pessac; Franck Morschhauser, Hôpital Claude Huriez, Lille, France; Don A. Stevens, Norton Cancer Institute, Louisville, KY; David Trevarthen, Comprehensive Cancer Care and Research Institute of Colorado, Englewood, CO; and Lisa Cupit, Li Liu, Carol Peña, Shuxin Yin, Jose Garcia-Vargas, and Barrett H. Childs, Bayer HealthCare Pharmaceuticals, Whippany, NJ.
J Clin Oncol. 2017 Dec 10;35(35):3898-3905. doi: 10.1200/JCO.2017.75.4648. Epub 2017 Oct 4.
Purpose Phosphatidylinositol 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-α and -δ isoforms, has demonstrated efficacy and a manageable safety profile in patients with indolent lymphoma. Patients and Methods In 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. Results Median 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. Conclusion PI3K-α and -δ inhibition by copanlisib demonstrated significant efficacy and a manageable safety profile in heavily pretreated patients with relapsed or refractory indolent lymphoma.
目的
磷脂酰肌醇 3-激酶（PI3K）信号对于恶性 B 细胞的增殖和存活至关重要。Copanlisib 是一种泛 I 类 PI3K 抑制剂，对 PI3K-α 和 -δ 同工型具有主要活性，在二线或多线治疗后复发或难治性惰性淋巴瘤患者中显示出疗效和可管理的安全性特征。
患者和方法
在这项 II 期研究中，招募了 142 名二线或多线治疗后复发或难治性惰性淋巴瘤患者，接受静脉注射 copanlisib 60 mg，每 28 天周期的第 1、8 和 15 天给药。主要终点是客观缓解率；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，还评估了安全性和基因表达。
结果
中位年龄为 63 岁（范围，25 至 82 岁），患者接受了中位数为三（范围，两至九）个先前的方案。客观缓解率为 59%（142 名患者中的 84 名）；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。最常见的治疗相关不良事件是短暂性高血糖（所有级别，50%；3 或 4 级，41%）和短暂性高血压（所有级别，30%；3 级，24%）。其他≥3 级事件包括中性粒细胞计数减少（24%）和肺部感染（15%）。Copanlisib 对 PI3K/B 细胞受体信号通路基因的高表达与高缓解率相关。
结论
Copanlisib 对 PI3K-α 和 -δ 的抑制在二线或多线治疗后复发或难治性惰性淋巴瘤的患者中显示出显著疗效和可管理的安全性特征。
