Avatrombopag for chemotherapy-induced thrombocytopenia in patients with non-haematological malignancies: an international, randomised, double-blind, placebo-controlled, phase 3 trial
Avatrombopag for chemotherapy-induced thrombocytopenia in patients with non-haematological malignancies: an international, randomised, double-blind, placebo-controlled, phase 3 trial
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Avatrombopag治疗非血液系统恶性肿瘤患者化疗诱导的血小板减少症：一项国际、随机、双盲、安慰剂对照、III期试验
DOI：
10.1016/s2352-3026(22)00001-1
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发表时间：
2022-03-01
影响因子：
24.7
通讯作者：
Jamieson, Brian D.
中科院分区：
文献类型：
--
作者：
Al-Samkari, Hanny;Kolb-Sielecki, Jaroslaw;Jamieson, Brian D.
化疗引起的血小板减少症是常见的，并导致化疗剂量减少或治疗延迟、出血和次优肿瘤结果。我们旨在评估avatrombopag,促血小板生成素受体激动剂,增加血小板计数,明确非癌症患者和血小板计数低于50每L.Methods x10(9)细胞在这种随机,双盲,安慰剂对照,三期研究中,患者在18岁或以上71家医院或癌症治疗中心在中国,匈牙利、波兰、俄罗斯、塞尔维亚、乌克兰和美国和卵巢,膀胱,接受化疗且伴有严重血小板减少症的肺癌患者被随机分配（2:1），化疗前后5天口服阿伐洛巴格60mg或口服安慰剂，每日一次，按化疗药物数量随机分层。患者、调查人员和数据收集人员被分组分配。资格要求既往接受过两条或更少的化疗，ECOG表现状态为2或更低，既往无化疗引起的血小板减少史。复合主要终点是不需要血小板输注或化疗剂量减少15%或更多或化疗延迟4天或更长时间的应答者的比例，因为研究治疗后血小板减少，直到下一个周期开始。对治疗意向和每个方案人群进行了分析。对所有接受了至少一剂阿凡洛巴的患者的安全性进行了分析。该试验已在ClinicalTrials.gov注册，编号NCT03471078，并已完成。在2018年10月12日至2020年6月28日期间，122名患者被纳入研究，并随机分配接受阿伐罗博帕（n=82）或安慰剂（n=40）治疗。中位随访时间为31天（IQR 22-61）。在阿伐罗巴格组和安慰剂组中，达到主要终点的患者比例相似(意向治疗：57 / 82 (70%,95% CI 58-79) vs 29 / 40 (73%, 95% CI 56-85)，差异为3.0% (95% CI -21.6 - 15.6)；p = 0.72;每个方案：51 / 60 (85%,95% CI 73-93) vs 27 / 32 (84%, 95% CI 67-95)；0.6% (95% CI -20.8 - 22.1)；p = 0.96)。阿伐罗巴格组82例患者中有15例（18%）发生严重不良事件，安慰剂组40例中有8例（20%）发生严重不良事件，其中血小板减少最为常见（82例中有4例[5%]，40例中有4例[10%]）。常见的3-4级治疗紧急不良事件为中性粒细胞减少（82例中有22例[27%]，40例中有16例[40%]）、白细胞减少（82例中有19例[23%]，40例中有5例[13%]）、贫血（82例中有16例[20%]，40例中有9例[23%]）和血小板减少（82例中有16例[20%]，40例中有14例[35%]）。大多数不良事件被认为与研究药物无关。没有与治疗相关的死亡报告。在这组相对化疗初期的非血液学恶性肿瘤患者中，化疗诱导的血小板减少治疗结果在阿伐洛巴格组和安慰剂组之间相似。鉴于它的安全性和增加化疗引起的血小板减少患者血小板计数的能力，在化疗引起的更持久的血小板减少人群中评估阿阿曲波帕是有必要的。爱思唯尔有限公司版权所有版权所有。
Background Chemotherapy-induced thrombocytopenia is common and causes chemotherapy dose reductions or treatment delays, bleeding, and suboptimal oncological outcomes. We aimed to evaluate avatrombopag, a thrombopoietin receptor agonist that increases platelet counts, in patients with non-haematological cancer and platelet counts lower than 50x10(9) cells per L.Methods In this randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18 years or older at 71 hospitals or cancer treatment centres in China, Hungary, Poland, Russia, Serbia, Ukraine, and the USA and with ovarian, bladder, or lung cancer receiving chemotherapy who had severe thrombocytopenia were randomly assigned (2:1) to oral avatrombopag 60 mg or oral placebo once daily given 5 days before and after chemotherapy, with randomisation stratified by number of chemotherapy drugs used. Patients, investigators, and data collectors were masked to group allocation. Eligibility required two previous lines of chemotherapy or fewer, an ECOG performance status of 2 or less, and no previous history of chemotherapy-induced thrombocytopenia. The composite primary endpoint was the proportion of responders not requiring platelet transfusion or either a 15% or more chemotherapy dose reduction or a 4-day or more chemotherapy delay due to thrombocytopenia following study treatment until the start of the subsequent cycle. Analyses were done on the intention-to-treat and per protocol populations. Safety was analysed in all patients who received at least one dose of avatrombopag. The trial is registered with ClinicalTrials.gov, NCT03471078, and has been completed.Findings Between Oct 12, 2018, and June 28, 2020, 122 patients were enrolled and randomly assigned to receive avatrombopag (n=82) or placebo (n=40). Median follow-up was 31 days (IQR 22-61). Similar proportions of patients reached the primary endpoint in the avatrombopag and placebo groups (intention-to-treat: 57 [70%, 95% CI 58-79] of 82 vs 29 [73%, 95% CI 56-85] of 40; difference -3.0% (95% CI -21.6 to 15.6); p=0.72; per protocol: 51 [85%, 95% CI 73-93] of 60 vs 27 [84%, 95% CI 67-95] of 32; 0.6% (95% CI -20.8 to 22.1); p=0.96). 15 (18%) of 82 patients had serious adverse events in the avatrombopag group and eight (20%) of 40 in the placebo group, of which thrombocytopenia was most common (4 [5%] of 82 and 4 [10%] of 40 patients). Common grade 3-4 treatment emergent adverse events were neutropenia (22 [27%] of 82 and 16 [40%] of 40 patients), leukopenia (19 [23%] of 82 and 5 [13%] of 40), anaemia (16 [20%] of 82 and 9 [23%] of 40), and thrombocytopenia (16 [20%] of 82 and 14 [35%] of 40). Most adverse events were considered unrelated to study drug. No treatment-related deaths were reported.Interpretation In this population of patients with non-haematological malignancies who are relatively chemotherapy naive, chemotherapy-induced thrombocytopenia treatment outcomes were similar between the avatrombopag and placebo groups. Given its safety and ability to augment platelet counts in patients with chemotherapy-induced thrombocytopenia, evaluation of avatrombopag in populations with more persistent chemotherapy-induced thrombocytopenia is warranted. Copyright (C) 2022 Elsevier Ltd. All rights reserved.