Rogel Cancer Center, University of Michigan, Ann Arbor, MI.
Institute of Hematology, Sheba Medical Center, Ramat Gan, Israel.
Blood Adv. 2024 Feb 27;8(4):867-877. doi: 10.1182/bloodadvances.2023010648.
Parsaclisib, a potent and highly selective PI3Kδ inhibitor, has shown clinical benefit in patients with relapsed or refractory (R/R) B-cell lymphomas. The phase 2 CITADEL-204 study (NCT03144674, EudraCT 2017-000970-12) assessed efficacy and safety of parsaclisib in Bruton tyrosine kinase (BTK) inhibitor-experienced (cohort 1) or BTK inhibitor-naive (cohort 2) patients with R/R marginal zone lymphoma (MZL). Patients aged ≥18 years with histologically confirmed R/R MZL, treated with ≥1 prior systemic therapy (including ≥1 anti-CD20 antibody) received parsaclisib 20 mg once daily for 8 weeks then 20 mg once weekly (weekly dosing group [WG]) or parsaclisib 20 mg once daily for 8 weeks then 2.5 mg once daily (daily dosing group [DG]); DG was selected for further assessment. Primary end point of the study was objective response rate (ORR). Owing to slower than expected recruitment, cohort 1 was closed with 10 patients (WG, n = 4; DG, n = 6) enrolled. Based on a planned interim analysis in cohort 2, the futility boundary was not crossed, and enrollment continued to study completion. At data cutoff (15 January 2021), 100 patients were enrolled and treated in cohort 2 (WG, n = 28; DG, n = 72). In the DG, the ORR was 58.3% (95% confidence interval [CI], 46.1-69.8), with a complete response rate of 4.2% (95% CI, 0.9-11.7); the lower bound of the ORR 95% CI exceeded the protocol-defined threshold of 40%. The median duration of response was 12.2 months (95% CI, 8.1-17.5) and progression-free survival was 16.5 months (95% CI, 11.5-20.6); median overall survival was not reached. The most common treatment-emergent adverse events (TEAEs) among all patients were diarrhea (47.0%), cough (23.0%), and rash (18.0%); the most common grade ≥3 TEAEs included diarrhea (12.0%), neutropenia, and pneumonia (9.0% each). TEAEs led to dose interruptions, reductions, and discontinuations in 56.0%, 16.0%, and 29.0% of all patients, respectively. Durable responses and an overall manageable safety profile were demonstrated in patients with R/R MZL treated with parsaclisib monotherapy.
帕萨昔布是一种有效的、高度选择性的 PI3Kδ 抑制剂，在复发或难治性（R/R）B 细胞淋巴瘤患者中显示出临床获益。这项 2 期 CITADEL-204 研究（NCT03144674，EudraCT 2017-000970-12）评估了帕萨昔布在 Bruton 酪氨酸激酶（BTK）抑制剂经治（队列 1）或 BTK 抑制剂初治（队列 2）的 R/R 边缘区淋巴瘤（MZL）患者中的疗效和安全性。年龄≥18 岁、组织学证实的 R/R MZL 患者，接受过≥1 种系统治疗（包括≥1 种抗 CD20 抗体），接受帕萨昔布 20mg 每日一次，连续 8 周，然后每周一次（每周剂量组[WG]）或帕萨昔布 20mg 每日一次，连续 8 周，然后每日一次 2.5mg（每日剂量组[DG]）；选择 DG 进行进一步评估。研究的主要终点为客观缓解率（ORR）。由于招募速度低于预期，队列 1入组 10 例患者（WG，n=4；DG，n=6）后关闭。基于队列 2 的计划中期分析，无效边界未被跨越，并且继续入组直至研究完成。数据截止日期（2021 年 1 月 15 日）时，队列 2 共入组并治疗了 100 例患者（WG，n=28；DG，n=72）。在 DG 中，ORR 为 58.3%（95%CI，46.1-69.8），完全缓解率为 4.2%（95%CI，0.9-11.7）；ORR 的 95%CI 下限超过了方案规定的 40%的阈值。中位缓解持续时间为 12.2 个月（95%CI，8.1-17.5），无进展生存期为 16.5 个月（95%CI，11.5-20.6）；中位总生存期未达到。所有患者中最常见的治疗相关不良事件（TEAE）是腹泻（47.0%）、咳嗽（23.0%）和皮疹（18.0%）；最常见的≥3 级 TEAE 包括腹泻（12.0%）、中性粒细胞减少和肺炎（各 9.0%）。所有患者中分别有 56.0%、16.0%和 29.0%的患者因 TEAEs 导致剂量中断、减少和停药。在接受帕萨昔布单药治疗的 R/R MZL 患者中，观察到持久缓解和总体可管理的安全性特征。
