小柯机器人

丹麦Rigshospitalet医院血液科Martin Hutchings团队研究了复发或难治性B细胞非霍奇金淋巴瘤患者皮下注射艾克瑞妥单抗剂量递增的疗效。相关论文发表在2021年9月8日出版的《柳叶刀》杂志上。

复发或难治性B细胞非霍奇金淋巴瘤患者的治疗选择很少。该研究旨在确定艾克瑞妥单抗的安全性和推荐的临床2期剂量，艾克瑞妥单抗是一类新型的针对CD3和CD20、并诱导T细胞介导的针对CD20+恶性B细胞的细胞毒活性的双特异性抗体。

对于该1/2期临床研究的剂量递增部分，研究组在4个国家（丹麦、荷兰、英国和西班牙）的10个机构招募复发或难治性CD20+ B细胞非霍奇金淋巴瘤的成年患者（年龄≥18岁）。符合条件的患者接受初始和中等剂量，然后在28天周期内接受全剂量皮下注射艾克瑞妥单抗；随后的每一组均涉及起始剂量、中间剂量或全剂量（0.0128–60 mg）的递增。主要目的是确定最大耐受剂量和推荐的临床2期剂量。此外还评估了安全性、抗肿瘤活性、药代动力学和免疫生物标志物。

2018年6月26日至2020年7月14日，研究组共登记了73例复发、进行性或难治性CD20+成熟B细胞非霍奇金淋巴瘤患者。68名患者接受逐步增加的全剂量（0.0128–60 mg）皮下注射艾克瑞妥单抗。未观察到剂量限制毒性作用，也未达到最大耐受剂量；48 mg的全剂量被确定为推荐的2期剂量。

所有68名患者均接受了至少一剂艾克瑞妥单抗，并纳入安全性分析：常见不良事件为发热（47名患者[69%]），主要与细胞因子释放综合征（CRS；40名[59%]，均为1-2级）和注射部位反应（32名[47%]；31名1级）有关。没有3级及以上的CRS事件。没有患者因治疗相关不良事件或治疗相关死亡而停药。

复发或难治性弥漫性大B细胞淋巴瘤患者的总有效率为68%，其中45%在12-60 mg的全剂量下达到完全缓解。48 mg剂量的总有效率为88%，38%达到完全缓解。复发或难治性滤泡性淋巴瘤患者的总有效率为90%，50%的患者在0.76–48 mg的全剂量下获得完全缓解。艾克瑞妥单抗可诱导B细胞持续消耗，CD4+和CD8+T细胞活化和扩增，细胞因子水平适度增加。

研究结果表明，单剂皮下注射艾克瑞妥单抗治疗复发或难治性B细胞非霍奇金淋巴瘤的1/2期临床试验疗效满意，值得继续进行2/3期研究。

附：英文原文

Title: Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study

Author: Martin Hutchings, Rogier Mous, Michael Roost Clausen, Peter Johnson, Kim M Linton, Martine E D Chamuleau, David John Lewis, Anna Sureda Balari, David Cunningham, Roberto S Oliveri, Brian Elliott, Dena DeMarco, Ada Azaryan, Christopher Chiu, Tommy Li, Kuo-mei Chen, Tahamtan Ahmadi, Pieternella J Lugtenburg

Issue&Volume: 2021-09-08

Abstract:

Background

Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have few treatment options. We aimed to establish the safety and recommended phase 2 dose of epcoritamab, a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells.

Methods

For the dose-escalation part of this phase 1/2 study, we enrolled adults (aged ≥18 years) with relapsed or refractory CD20+ B-cell non-Hodgkin lymphoma at ten sites across four countries (Denmark, the Netherlands, the UK, and Spain). Eligible patients received priming and intermediate doses followed by full doses of subcutaneous epcoritamab administered in 28-day cycles; each subsequent cohort involved escalation of the priming, intermediate, or full dose (0·0128–60 mg). The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Safety, antitumour activity, pharmacokinetics, and immune biomarkers were also assessed. This study is registered with ClinicalTrials.gov, NCT03625037, with the dose-expansion part ongoing.

Findings

Between June 26, 2018, and July 14, 2020, we enrolled 73 patients with relapsed, progressive, or refractory CD20+ mature B-cell non-Hodgkin lymphoma. 68 patients received escalating full doses (0·0128–60 mg) of subcutaneous epcoritamab. No dose-limiting toxic effects were observed, and the maximum tolerated dose was not reached; the full dose of 48 mg was identified as the recommended phase 2 dose. All 68 patients received at least one dose of epcoritamab and were included in safety analyses: common adverse events were pyrexia (47 patients [69%]), primarily associated with cytokine release syndrome (CRS; 40 [59%], all grade 1–2), and injection site reactions (32 [47%]; 31 grade 1). There were no grade 3 or higher CRS events. No discontinuations occurred due to treatment-related adverse events or treatment-related deaths. Overall response rate in patients with relapsed or refractory diffuse large B-cell lymphoma was 68% (95% CI 45–86), with 45% achieving a complete response at full doses of 12–60 mg. At 48 mg, the overall response rate was 88% (47–100), with 38% achieving a complete response. Patients with relapsed or refractory follicular lymphoma had an overall response rate of 90% (55–100), with 50% achieving a complete response at full doses of 0·76–48 mg. Epcoritamab induced robust and sustained B-cell depletion, and CD4+ and CD8+ T-cell activation and expansion, with modest increases in cytokine levels.

Interpretation

Single-agent subcutaneous epcoritamab for treatment of patients with relapsed or refractory B-cell non-Hodgkin lymphoma merits investigation in ongoing phase 2 and phase 3 studies.

DOI: 10.1016/S0140-6736(21)00889-8

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00889-8/fulltext

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