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：对多中心、开放标签、1/2 期 BRUIN 研究中的里氏转化亚组进行分析


里氏转化通常表现为侵袭性弥漫性大 B 细胞淋巴瘤，发生在高达 10% 的慢性淋巴细胞白血病患者中，目前尚无批准的治疗方法，且预后不良。 Pirtobrutinib 在复发或难治性 B 细胞恶性肿瘤患者（包括那些使用共价布鲁顿酪氨酸激酶 (BTK) 抑制剂治疗后进展的患者）中显示出良好的疗效和耐受性。本研究旨在报告多中心、开放标签、1/2 期 BRUIN 研究中 pirtobrutinib 单药治疗在患有 Richter 转化的患者亚组中的安全性和活性。该分析包括组织学证实的里氏转化、东部肿瘤合作组表现状态评分为 0-2 分且既往治疗不受限制的成年患者（年龄≥18 岁），并在方案修正案中添加了接受一线治疗的患者（版本 9.0，2021 年 12 月 15 日）。 Pirtobrutinib 200 mg 以 28 天为一个周期，每天口服一次。之前曾报道过，BRUIN 试验整体 1 期的主要终点是确定 pirtobrutinib 单药治疗的推荐 2 期剂量，2 期主要终点是总体缓解率。对接受至少一剂吡托布替尼单药治疗的所有患者的安全性和活性进行了测量。该 BRUIN 1/2 期试验已在 () 注册并已结束招募。 2019年12月26日至2022年7月22日期间，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。除一名患者外，所有患者均接受每天一次200 mg pirtobrutinib的起始剂量作为推荐阶段2剂。另一名患者每天接受 150 毫克吡托布替尼治疗，但剂量并未升级至 200 毫克。 患者的中位年龄为 67 岁（IQR 59-72）。 82 名患者中有 55 名 (67%) 为男性，27 名 (33%) 为女性。大多数患者是白人（82 名患者中的 65 名 [79%]）。 82 名患者中有 74 名 (90%) 接受过至少一种先前的里氏转化导向治疗。大多数患者（82 名患者中的 61 名 [74%]）之前曾接受过共价 BTK 抑制剂治疗慢性淋巴细胞白血病或里氏转化。总体缓解率为 50·0% (95% CI 38·7–61·3)。 82 名患者中有 11 名（13%）有完全缓解，82 名患者中有 30 名（37%）有部分缓解。八名持续缓解的患者选择性地停止接受吡托布替尼治疗以接受干细胞移植。最常见的 3 级或更严重不良事件是中性粒细胞减少症 (n=19)。没有出现与治疗相关的死亡。 Pirtobrutinib 在 Richter 转化患者中显示出良好的安全性和活性，其中大多数患者之前接受过 Richter 转化导向治疗，包括共价 BTK 抑制剂。这些数据表明，有必要进一步研究吡托布替尼作为共价 BTK 抑制剂治疗后复发或难治性里氏转化患者的治疗选择。洛克索肿瘤学。