Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study
Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study
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DOI：
10.1016/s0140-6736(21)00224-5
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发表时间：
2021-03-06
期刊：
影响因子：
168.9
通讯作者：
Wang, Michael
中科院分区：
文献类型：
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作者：
Mato, Anthony R.;Shah, Nirav N.;Wang, Michael
背景共价布鲁顿酪氨酸激酶 (BTK) 抑制剂对多种 B 细胞恶性肿瘤有效，但患者因耐药和不耐受而停止使用这些药物。我们评估了 pirtobrutinib（工作名称；以前称为 LOXO-305）（一种高选择性、可逆的 BTK 抑制剂）在这些患者中的安全性和有效性。方法将先前接受过治疗的 B 细胞恶性肿瘤患者纳入 BTK 抑制剂 pirtobrutinib 的首次人体、多中心、开放标签、1/2 期试验。主要终点是最大耐受剂量（1 期）和总体缓解率（ORR；2 期）。该试验已在 ClinicalTrials.gov 注册，NCT03740529。结果 323 名患者接受了 7 个剂量水平（25 mg、50 mg、100 mg、150 mg、200 mg、250 mg 和 300 mg 每天一次）的 pirtobrutinib 治疗，暴露量呈线性剂量比例。没有观察到剂量限制性毒性并且未达到最大耐受剂量。推荐的 2 期剂量为每天 200 毫克。 323 名患者中至少 10% 的不良事件为疲劳 (65 [20%])、腹泻 (55 [17%]) 和挫伤 (42 [13%])。最常见的 3 级或以上不良事件是中性粒细胞减少症 (32 [10%])。吡托布替尼暴露与 3 级治疗相关不良事件的频率之间没有相关性。未观察到 3 级心房颤动或扑动，1 名患者在机械创伤情况下观察到 3 级出血。五名 (1%) 患者因治疗相关不良事件而停止治疗。在 121 名可评估疗效的慢性淋巴细胞白血病 (CLL) 或小淋巴细胞淋巴瘤 (SLL) 患者中，曾接受过共价 BTK 抑制剂治疗（既往治疗线中位数为 4），吡托布替尼的 ORR 为 62% (95% CI 53-71)。先前对共价 BTK 抑制剂耐药（79 例中的 53 例 [67%]）、共价 BTK 抑制剂不耐受（42 例中的 22 例 [52%]）、BTK C481 突变体（24 例中的 17 例 [71%]）和 BTK 野生型（65 例中的 43 例 [66%]）疾病的 CLL 患者的 ORR 相似。在 52 名既往接受共价 BTK 抑制剂治疗的可评估疗效的套细胞淋巴瘤 (MCL) 患者中，ORR 为 52% (95% CI 38-66)。在 117 名出现缓解的 CLL、SLL 或 MCL 患者中，除 8 名外，迄今为止，所有患者均未出现进展。 解释 Pirtobrutinib 在多种 B 细胞恶性肿瘤（包括之前接受共价 BTK 抑制剂治疗的患者）中是安全且有效的。 Pirtobrutinib 可能会解决这些患者对替代疗法日益增长的未满足的需求。版权所有 (C) 2021 爱思唯尔有限公司。保留所有权利。
Background Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients.Methods Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/ 2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529.Findings 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date.Interpretation Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients. Copyright (C) 2021 Elsevier Ltd. All rights reserved.