Loncastuximab tesirine
[Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2):
a multicentre, open-label, single-arm, phase 2 trial]
Paolo F Caimi, et al; Lancet Oncol. 2021 Jun;22(6):790-800.
Abstract
Background: Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not respond to or who have progressive disease after salvage therapies have a poor prognosis. Loncastuximab tesirine is a CD19-directed antibody-drug conjugate with encouraging phase 1 single-agent antitumour activity and acceptable safety in non-Hodgkin lymphoma. We aimed to evaluate the antitumour activity and safety of loncastuximab tesirine in patients with relapsed or refractory DLBCL.
Methods: We did a multicentre (28 hospital sites in the USA, UK, Italy, and Switzerland), open-label, single-arm, phase 2 trial (LOTIS-2) in patients aged 18 years or older with relapsed or refractory DLBCL after two or more multiagent systemic treatments, who had measurable disease and Eastern Cooperative Oncology Group performance status 0-2. Eligible patients received loncastuximab tesirine intravenously on day 1 of each 21-day cycle, at 150 μg/kg for two cycles, then 75 μg/kg thereafter, for up to 1 year or until disease relapse or progression, unacceptable toxicity, death, major protocol deviation, pregnancy, or patient, investigator, or sponsor decision. The primary endpoint was overall response rate assessed by central review. Primary antitumour activity and safety analyses were done in the as-treated population (patients who received at least one dose of loncastuximab tesirine), when all responding patients had at least 6 months of follow-up after initial documented response. Enrolment is complete. This trial is registered with ClinicalTrials.gov, NCT03589469.
Findings: Between Aug 1, 2018, and Sept 24, 2019, 184 patients were assessed for eligibility and 145 (79%) were enrolled and received at least one dose of loncastuximab tesirine, including patients with high-risk characteristics for poor prognosis, such as double-hit, triple-hit, transformed, or primary refractory DLBCL. 70 of 145 patients had complete or partial response (overall response rate 48·3% [95% CI 39·9-56·7]); 35 had complete response and 35 had partial response. The most common grade 3 or higher treatment-emergent adverse events were neutropenia (37 [26%] of 145 patients), thrombocytopenia (26 [18%]), and increased gamma-glutamyltransferase (24 [17%]). Serious adverse events were reported in 57 (39%) of 145 patients. Treatment-emergent adverse events with a fatal outcome occurred in eight (6%) of 145 patients; none were considered related to loncastuximab tesirine.
Interpretation: Loncastuximab tesirine has substantial single-agent antitumour activity and produces durable responses with an acceptable safety profile, potentially offering a new therapeutic option for heavily pretreated patients with relapsed or refractory DLBCL.
[龙卡西单抗替西林Loncastuximab tesirine治疗复发或难治性弥漫性大B细胞淋巴瘤（LOTIS-2）] 。
Paolo F Caimi, et al; Lancet Oncol. 2021 June: 22(6):790-800.
摘要
背景~复发或难治性弥漫性大B细胞淋巴瘤（DLBCL）患者在接受挽救性治疗后无反应或疾病进展，其预后不佳。龙卡西单抗替西林(Loncastuximab tesirine)是一种CD19导向的抗体-药物结合物，在非霍奇金淋巴瘤中具有令人鼓舞的1期单药抗肿瘤活性和可接受的安全性。我们旨在评估龙卡西单抗替西林对复发或难治性DLBCL患者的抗肿瘤活性和安全性。
方法~我们进行了一项多中心（美国、英国、意大利和瑞士的28家医院）、开放标签、单臂、2期试验（LOTIS-2），试验对象为18岁或以上、经过两次或多次多药系统治疗的复发或难治性DLBCL患者，他们有可测量的疾病，ECOG表现状态为0-2。符合条件的患者在每个21天周期的第1天静脉注射龙卡西单抗替西林，两个周期为150μg/kg，此后为75μg/kg，持续1年或直到疾病复发或进展。主要终点是总反应率。主要的抗肿瘤活性和安全性分析是在接受治疗的人群中进行的（至少接受一剂长春瑞滨的患者），当所有应答的患者在最初记录的应答后有至少6个月的随访。
研究结果~在2018年8月1日至2019年9月24日期间，对184名患者进行了资格评估，145名（79%）入组并接受了至少一剂龙卡西单抗替西林，包括具有预后不佳的高风险特征的患者，如双击、三击、转化或原发性难治性DLBCL。145名患者中有70人完全或部分反应（总反应率48-3%[95% CI 39-9-56-7]）；35人完全反应，35人部分反应。最常见的3级或更高等级的治疗不良事件是中性粒细胞减少（145名患者中的37人[26%]）、血小板减少（26人[18%]）和γ-谷氨酰转肽酶增加（24人[17%]）。145名患者中有57人（39%）报告了严重的不良事件。145名患者中有8名（6%）发生了具有致命结果的治疗突发不良事件；没有人认为与龙卡西单抗替西林有关。
解释~龙卡西单抗替西林具有单药抗肿瘤活性，并能产生持久的反应，同时具有可接受的安全性，有可能为复发或难治性DLBCL的重度预处理患者提供新的治疗选择。
