Parsaclisib是一种强效且高选择性的PI3Kδ抑制剂，在复发/难治（R/R）B细胞恶性肿瘤患者中显示出临床益处。在这个第二阶段研究（CITADEL-205; NCT03235544, EudraCT 2017-003148-19）中，我们评估了Parsaclisib在R/R曼托细胞淋巴瘤（MCL）患者中的疗效和安全性。年龄≥18岁的病理学上确诊的R/R MCL患者，并且曾接受1-3个系统治疗，其中一个亚组（亚组1）接受过布鲁顿激酶抑制剂（BTKi）治疗，另一个亚组（亚组2）未接受BTKi治疗，亚组1接受20mg口服Parsaclisib每日一次（QD）治疗8周，然后转为每周一次20mgParsaclisib（每周用药组[WG]）或每日一次2.5mgParsaclisib（每日用药组[DG]），亚组2在治疗方式上与亚组1相同。主要终点为客观反应率（ORR）。在2021年1月15日的首次分析数据截止时，53名亚组1患者（BTKi经验者）（WG，n = 12；DG：n = 41）和108名亚组2患者（BTKi未经验者）（WG，n = 31；DG：n = 77）接受了Parsaclisib单药治疗。亚组1（BTKi经验者）由于中期分析显示临床效益有限而关闭。在BTKi未经验者亚组中，DG组（选择进一步研究的给药方式）的ORR（95％CI）为70.1％（58.6％- 80.0％），完全缓解率（95％CI）为15.6％（8.3％-25.6％），反应持续时间的中位数（95％CI）为12.1个月（9.0-无法评估）。BTKi未经验者亚组中，所有接受治疗的患者中有90.7％（108/108）出现治疗相关的不良事件（TEAEs）。其中62.0％（67/108）的患者出现≥3级TEAEs，包括腹泻（13.9％，15/108）和中性粒细胞减少症（8.3％，9/108）。Parsaclisib由于TEAEs而导致的中断、减量或停药分别发生在47.2％（51/108）、8.3％（9/108）和25.0％（27/108）的患者中。六名患者出现了致命的TEAEs，其中一名患者被确定为与治疗相关。Parsaclisib，一种强效、高选择性的PI3Kδ抑制剂，在无先前BTKi治疗的R/R MCL患者中显示出有意义的临床益处和可管理的安全性（25.0％的停药率，个体报告的≥3级或严重不良事件的发生率低）。已接受BTKi治疗的患者在Parsaclisib单药治疗中观察到有限的临床益处。未来开发针对非霍奇金淋巴瘤的PI3K抑制剂需要进一步研究剂量优化以改善安全性和长期生存。Incyte公司。© 2023 作者们。

Parsaclisib is a potent and highly selective PI3Kδ inhibitor that has shown clinical benefit in patients with relapsed/refractory (R/R) B-cell malignancies. In this phase 2 study (CITADEL-205; NCT03235544, EudraCT 2017-003148-19), the efficacy and safety of parsaclisib was evaluated in patients with R/R mantle cell lymphoma (MCL).Patients ≥18 years old with pathologically confirmed R/R MCL and prior treatment with 1-3 systemic therapies, with (cohort 1) or without (cohort 2) previous Bruton kinase inhibitor (BTKi) treatment, received oral parsaclisib 20 mg once-daily (QD) for 8 weeks, then either parsaclisib 20 mg once-weekly (weekly dosing group [WG]) or parsaclisib 2.5 mg QD (daily dosing group [DG]). The primary endpoint was objective response rate (ORR).At the primary analysis data cutoff on January 15, 2021, 53 patients in cohort 1 (BTKi-experienced) (WG, n = 12; DG: n = 41) and 108 patients in cohort 2 (BTKi-naive) (WG, n = 31; DG: n = 77) had received parsaclisib monotherapy. The BTKi-experienced cohort was closed after an interim analysis demonstrated limited clinical benefit. In the BTKi-naive cohort, the ORR (95% CI) for DG (dosing selected for further study) was 70.1% (58.6%-80.0%), with a complete response rate (95% CI) of 15.6% (8.3%-25.6%) and a median duration of response (95% CI) of 12.1 (9.0-not evaluable) months. Treatment-emergent adverse events (TEAEs) occurred among 90.7% (98/108) of all treated patients in the BTKi-naive cohort. Grade ≥3 TEAEs occurred among 62.0% (67/108) of patients, including diarrhoea (13.9%, 15/108) and neutropenia (8.3%, 9/108). Parsaclisib interruption, reduction, or discontinuation due to TEAEs occurred among 47.2% (51/108), 8.3% (9/108), and 25.0% (27/108) of patients, respectively. Fatal TEAEs were experienced by six patients and determined to be treatment-related in one patient.Parsaclisib, a potent, highly selective, PI3Kδ inhibitor demonstrated meaningful clinical benefits and a manageable safety profile (25.0% discontinuation rate, low incidences of individually reported grade ≥3 or serious adverse events) in R/R MCL patients with no prior BTKi therapy. Limited clinical benefit was observed with parsaclisib monotherapy in patients who had previously received BTKi treatment. Future development of PI3K inhibitors for NHL will require further investigation of dose optimisation to improve safety and long-term survival.Incyte Corporation.© 2023 The Authors.