美国纪念斯隆·凯特琳癌症中心Anthony R Mato团队研究了pirtobrutinib治疗复发或难治性B细胞恶性肿瘤的临床1、2期疗效。2021年3月6日，《柳叶刀》杂志发表了该成果。

共价Bruton酪氨酸激酶（BTK）抑制剂对多种B细胞恶性肿瘤有效，但由于耐药和不耐受，患者停止使用这些药物。研究组评估了pirtobrutinib（原名LOXO-305，一种高选择性、可逆的BTK抑制剂）的安全性和有效性。

研究组进行了一项首次人体内、多中心、开放标签、1/2期临床试验，招募先前接受过治疗的B细胞恶性肿瘤患者。主要终点是最大耐受剂量（临床1期）和总有效率（ORR，临床2期）。

323名患者接受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，剂量比例为线性暴露。未观察到剂量限制毒性，也未达到最大耐受剂量。建议临床2期剂量为每日200 mg。323名患者中至少有10%发生不良事件，包括疲劳、腹泻和挫伤。最常见的3级及以上不良事件是中性粒细胞减少（32名[10%]）。Pirtobrutinib暴露与3级治疗相关不良事件发生率之间没有相关性。

未观察到3级心房颤动或扑动，1例机械创伤患者出现3级出血。5（1%）名患者因治疗相关的不良事件而停止治疗。在121例接受过共价BTK抑制剂治疗的慢性淋巴细胞白血病（CLL）或小淋巴细胞淋巴瘤（SLL）的疗效可评价患者中，pirtobrutinib的ORR为62%。

既往有共价BTK抑制剂耐药（67%），共价BTK抑制剂不耐受（52%），BTK C481突变体（71%）和BTK野生型（66%）的CLL患者的ORR均相差不大。在52例先前接受过共价BTK抑制剂治疗的套细胞淋巴瘤（MCL）患者中，ORR为52%。117例CLL、SLL或MCL患者中获得缓解者，除8例外，其余患者至今无疾病进展。

研究结果表明，pirtobrutinib对多种B细胞恶性肿瘤安全有效，包括先前接受过共价BTK抑制剂治疗的患者。

附：英文原文

Title: Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study

Author: Anthony R Mato, Nirav N Shah, Wojciech Jurczak, Chan Y Cheah, John M Pagel, Jennifer A Woyach, Bita Fakhri, Toby A Eyre, Nicole Lamanna, Manish R Patel, Alvaro Alencar, Ewa Lech-Maranda, William G Wierda, Catherine C Coombs, James N Gerson, Paolo Ghia, Steven Le Gouill, David John Lewis, Suchitra Sundaram, Jonathon B Cohen, Ian W Flinn, Constantine S Tam, Minal A Barve, Bryone Kuss, Justin Taylor, Omar Abdel-Wahab, Stephen J Schuster, M Lia Palomba, Katharine L Lewis, Lindsey E Roeker, Matthew S Davids, Xuan Ni Tan, Timothy S Fenske, Johan Wallin, Donald E Tsai, Nora C Ku, Edward Zhu, Jessica Chen, Ming Yin, Binoj Nair, Kevin Ebata, Narasimha Marella, Jennifer R Brown, Michael Wang

Issue&Volume: 2021/03/06

Abstract:

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.

DOI: 10.1016/S0140-6736(21)00224-5

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00224-5/fulltext