Richter transformation usually presents as an aggressive diffuse large B-cell lymphoma, occurs in up to 10% of patients with chronic lymphocytic leukaemia, has no approved therapies, and is associated with a poor prognosis. Pirtobrutinib has shown promising efficacy and tolerability in patients with relapsed or refractory B-cell malignancies, including those who progress on covalent Bruton tyrosine kinase (BTK) inhibitors. This study aims to report the safety and activity of pirtobrutinib monotherapy in a subgroup of patients with Richter transformation from the multicentre, open-label, phase 1/2 BRUIN study. This analysis included adult patients (aged ≥18 years) with histologically confirmed Richter transformation, an Eastern Cooperative Oncology Group performance status score of 0–2, and no limit of previous therapies, with patients receiving first-line treatment added in a protocol amendment (version 9.0, Dec 15, 2021). Pirtobrutinib 200 mg was administered orally once a day in 28-day cycles. The primary endpoint of phase 1 of the BRUIN trial as a whole, which has been previously reported, was to establish the recommended phase 2 dose for pirtobrutinib monotherapy and the phase 2 primary endpoint was overall response rate. Safety and activity were measured in all patients who received at least one dose of pirtobrutinib monotherapy. This BRUIN phase 1/2 trial was registered with and is closed to enrolment (). Between Dec 26, 2019, and July 22, 2022, 82 patients were enrolled, of whom five were enrolled during phase 1 and 77 during phase 2. All but one patient received a starting dose of 200 mg pirtobrutinib once a day as the recommended phase 2 dose. The remaining patient received 150 mg pirtobrutinib once a day, which was not escalated to 200 mg. The median age of patients was 67 years (IQR 59–72). 55 (67%) of 82 patients were male and 27 (33%) were female. Most patients were White (65 [79%] of 82). 74 (90%) of 82 patients received at least one previous Richter transformation-directed therapy. Most patients (61 [74%] of 82) had received previous covalent BTK inhibitor therapy for chronic lymphocytic leukaemia or Richter transformation. The overall response rate was 50·0% (95% CI 38·7–61·3). 11 (13%) of 82 patients had a complete response and 30 (37%) of 82 patients had a partial response. Eight patients with ongoing response electively discontinued pirtobrutinib to undergo stem-cell transplantation. The most common grade 3 or worse adverse event was neutropenia (n=19). There were no treatment-related deaths. Pirtobrutinib shows promising safety and activity among patients with Richter transformation, most of whom received previous Richter transformation-directed therapy, including covalent BTK inhibitors. These data suggest that further investigation is warranted of pirtobrutinib as a treatment option for patients with relapsed or refractory Richter transformation after treatment with a covalent BTK inhibitor. Loxo Oncology.

中文翻译：

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Pirtobrutinib，一种用于 B 细胞恶性肿瘤患者的高选择性、非共价（可逆）BTK 抑制剂：来自多中心、开放标签、1/2 期 BRUIN 研究的 Richter 转化亚组分析


里氏转化通常表现为侵袭性弥漫性大 B 细胞淋巴瘤，见于高达 10% 的慢性淋巴细胞白血病患者，没有批准的治疗方法，并且与不良预后相关。吡托布替尼在复发或难治性 B 细胞恶性肿瘤患者中显示出有希望的疗效和耐受性，包括那些使用共价布鲁顿酪氨酸激酶 （BTK） 抑制剂后进展的患者。本研究旨在报告 pirtobrutinib 单药治疗在多中心、开放标签、1/2 期 BRUIN 研究的 Richter 转化患者亚组中的安全性和活性。该分析包括经组织学证实的 Richter 转化的成年患者 （≥18 岁），Eastern Cooperative Oncology Group 体能状态评分为 0-2，既往治疗没有限制，接受一线治疗的患者在方案修正案（9.0 版，2021 年 12 月 15 日）中增加。Pirtobrutinib 200 mg 以 28 天的周期每天口服一次。之前已经报道过的整个 BRUIN 试验的 1 期主要终点是确定吡托替尼单药治疗的推荐 2 期剂量，2 期主要终点是总缓解率。测量了所有接受至少一剂 pirtobrutinib 单药治疗的患者的安全性和活性。这项 BRUIN 1/2 期试验已在 （） 注册并已关闭入组 （）。在 2019 年 12 月 26 日至 2022 年 7 月 22 日期间，共入组了 82 名患者，其中 5 名患者在第 1 阶段入组，77 名患者在第 2 阶段入组。除 1 名患者外，所有患者均接受 200 mg pirtobrutinib 的起始剂量，每天一次，作为推荐的 2 期剂量。其余患者接受 150 mg pirtobrutinib 每天一次，未升级至 200 mg。 患者的中位年龄为 67 岁 （IQR 59-72）。82 例患者中有 55 例 （67%） 为男性，27 例 （33%） 为女性。大多数患者是白人 （82 人中的 65 人 [79%]）。82 例患者中有 74 例 （90%） 既往接受过至少一种 Richter 转化定向治疗。大多数患者 （82 例中的 61 例 [74%] ] 既往接受过慢性淋巴细胞白血病或里氏转化的共价 BTK 抑制剂治疗。总缓解率为 50·0% （95% CI 38·7–61·3）。82 例患者中有 11 例 （13%） 有完全缓解，82 例患者中有 30 例 （37%） 有部分缓解。8 例持续反应的患者选择性停用 pirtobrutinib 接受干细胞移植。最常见的 3 级或更严重的不良事件是中性粒细胞减少症 （n=19）。没有与治疗相关的死亡。吡托布替尼在里氏转化患者中显示出良好的安全性和活性，其中大多数患者既往接受过里氏转化定向治疗，包括共价 BTK 抑制剂。这些数据表明，有必要进一步研究 pirtobrutinib 作为共价 BTK 抑制剂治疗后复发或难治性 Richter 转化患者的治疗选择。Loxo 肿瘤学。