Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (ARROW): interim analysis results of a randomised, phase 3 study
Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (ARROW): interim analysis results of a randomised, phase 3 study
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DOI：
10.1016/s1470-2045(18)30354-1
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发表时间：
2018-07-01
期刊：
影响因子：
51.1
通讯作者：
Stewart, A. Keith
中科院分区：
文献类型：
--
作者：
Moreau, Philippe;Mateos, Maria-Victoria;Stewart, A. Keith
背景 每周两次 27 mg/m(2) 卡非佐米被批准用于治疗复发性或难治性多发性骨髓瘤。 1/2 期 CHAMPION-1 是第一项探索每周一次卡非佐米给药的研究，确定了与地塞米松联合使用的最大耐受剂量为 70 mg/m(2)。我们的目的是比较每周一次卡非佐米或每周两次卡非佐米治疗的复发难治性多发性骨髓瘤患者的无进展生存期。在这项试验中，我们从医院、诊所、肿瘤科或医疗中心招募了患有复发性难治性多发性骨髓瘤的患者（年龄 18 岁及以上），这些患者之前曾接受过两种或三种治疗方法，包括蛋白酶体抑制剂和免疫调节剂。关键资格标准是对最近的治疗（包括硼替佐米或伊沙佐米）无效且可测量疾病，且东部肿瘤合作组表现状态为 0 或 1。患者被随机分配 (1:1) 接受每周一次卡非佐米 (70 mg/m(2)) 或每周两次 (27 mg/m(2))。随机化序列是使用经过验证的随机化软件生成的，并使用交互式响应技术系统实施的，当患者在参与的临床中心入组时，该系统根据随机化序列将患者依次分配至治疗。根据研究开始时或基线时的国际分期系统分期、患者是否对硼替佐米治疗难治以及年龄（区块大小为 4）对患者进行分层。每周一次的组在所有周期的第 1、8 和 15 天接受卡非佐米（30 分钟静脉输注）（第 1 天 20 mg/m(2) [第 1 周期]；此后 70 mg/m(2)）。每周两次的组在第 1、2、8、9、15 和 16 天接受卡非佐米（10 分钟静脉输注）（第 1 周期第 1 和第 2 天 20 mg/m(2)；此后 27 mg/m(2)）。所有患者均接受地塞米松治疗（第 1 天、第 8 天、第 15 天[所有周期]和第 22 天[仅第 1-9 个周期]服用 40 mg）。治疗持续直至疾病进展或出现不可接受的毒性作用。主要目的是比较意向治疗人群中各组之间的无进展生存期。对所有接受至少一剂研究治疗的随机分配的患者进行安全性分析。该试验已在 ClinicalTrials.gov 注册，编号为 NCT02412878，并且不再招募患者。调查结果 2015 年 9 月至 2016 年 8 月期间，从 118 个地点招募了 578 名患者。 478 名患者被随机分配并纳入疗效分析（240 名患者接受每周一次卡非佐米；238 名患者接受每周两次卡非佐米）。每周一次组的中位无进展生存期高于每周两次组（11.2 个月 [95% CI 8.6-13.0] vs 7.6 个月 [5.8-9.2]；风险比 [HR] 0.69，95% CI 0.54-0.83；p=0.0029）。每周一次组的 3 级或更严重不良事件发生率高于每周两次组（68% [n=161] vs 62% [n=145]）；最常见的事件是贫血、肺炎和血小板减少症（每周一次卡非佐米与每周两次卡非佐米分别为 42 [18%] vs 42 [18%]、24 [10%] vs 16 [7%] 和 17 [7%] vs 16 [7%]）。每周一次组中患有 3 级或更严重心力衰竭的患者比例 (7 [3%]) 低于每周两次组 (10 [4%])。每周一次组的 238 名患者中有 5 名 (2%) 发生治疗相关死亡（败血症 [n=1]、死亡 [n=1]、急性肺损伤 [n=1]、急性呼吸窘迫综合征 [n=1] 和肿瘤溶解综合征 [n=1]），每周两次组 235 名患者中有 2 名 (1%) 发生治疗相关死亡（浆细胞骨髓瘤 [n=1] 和充血性心力衰竭 [n=1]）。截至数据截止时，每周一次组有 58 例死亡，每周两次组有 68 例死亡。 解释 与每周两次方案相比，每周一次 70 mg/m(2) 卡非佐米显着延长了无进展生存期。各组之间的总体安全性相当。与每周两次的方案相比，每周一次的卡非佐米在治疗复发性和难治性多发性骨髓瘤患者方面似乎更安全、更有效，且给药方案方便。版权所有 (c) 2018 Elsevier Ltd. 保留所有权利。
Background Twice a week carfilzomib at 27 mg/m(2) is approved for treatment of relapsed or refractory multiple myeloma. Phase 1/2 CHAMPION-1, the first study exploring once-weekly carfilzomib dosing, established the maximum tolerated dose at 70 mg/m(2) in combination with dexamethasone. We aimed to compare progression-free survival in patients with relapsed and refractory multiple myeloma given once weekly carfilzomib or twice weekly carfilzomib.Methods In this prespecified interim analysis of the randomised, open-label, phase 3 A.R.R.O.W. trial, we recruited patients (aged 18 years and older) with relapsed and refractory multiple myeloma previously treated with two or three treatments, including a proteasome inhibitor and immunomodulatory agent, from hospital, clinic, oncology or medical centres. Key eligibility criteria were refractory to most recent therapy (including bortezomib or ixazomib) with measurable disease, and Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were randomly assigned (1: 1) to receive carfilzomib once a week (70 mg/m(2)) or twice a week (27 mg/m(2)). The randomisation sequence was generated using a validated randomisation software and implemented using an interactive response technology system that assigned patients to treatment sequentially based on the randomisation sequence as patients were enrolled at participating clinical sites. Patients were stratified by International Staging System stage at study entry or baseline, whether or not they were refractory to bortezomib treatment, and age (block size of 4). The once weekly group received carfilzomib (30 min intravenous infusion) on days 1, 8, and 15 of all cycles (20 mg/m(2) day 1 [cycle 1]; 70 mg/m(2) thereafter). The twice weekly group received carfilzomib (10 min intravenous infusion) on days 1, 2, 8, 9, 15, and 16 (20 mg/m(2) days 1 and 2 during cycle 1; 27 mg/m(2) thereafter). All patients received dexamethasone (40 mg on days 1, 8, 15 [all cycles] and 22 [cycles 1-9 only]). Treatment continued until disease progression or unacceptable toxic effects. The primary objective was to compare progression-free survival between groups in the intention-to-treat population. Safety analysis was done in all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02412878, and is no longer enrolling patients.Findings Between September, 2015, and August, 2016, 578 patients were recruited from 118 sites. 478 patients were randomly assigned and included in the efficacy analyses (240 to receive once weekly carfilzomib; 238 to receive twice weekly carfilzomib). Median progression-free survival was higher in the once weekly group than the twice weekly group (11.2 months [95% CI 8.6-13.0] vs 7.6 months [5.8-9.2]; hazard ratio [HR] 0.69, 95% CI 0.54-0.83; p=0.0029). The incidence of grade 3 or worse adverse events was higher in the once weekly group than the twice weekly group (68% [n=161] vs 62% [n=145]); the most common events were anaemia, pneumonia, and thrombocytopenia (42 [18%] vs 42 [18%], 24 [10%] vs 16 [7%], and 17 [7%] vs 16 [7%], respectively for once weekly carfilzomib vs twice weekly carfilzomib). A lower proportion of patients had grade 3 or worse cardiac failure in the once weekly group (7 [3%]) than in the twice weekly group (10 [4%]). Treatment-related deaths occurred in five (2%) of 238 patients in the once weekly group (sepsis [n=1], death [n=1], acute lung injury [n=1], acute respiratory distress syndrome [n=1], and tumour lysis syndrome [n=1]) and in two (1%) of 235 patients in the twice weekly group (plasma cell myeloma [n=1] and congestive heart failure [n=1]). There were 58 deaths in the once weekly group and 68 deaths in the twice weekly group at the time of data cutoff.Interpretation Once weekly carfilzomib at 70 mg/m(2) significantly prolonged progression-free survival versus the twice weekly schedule. Overall safety was comparable between the groups. Once weekly carfilzomib appears safe and more effective with a convenient dosing regimen versus the twice weekly schedule for the treatment of patients with relapsed and refractory multiple myeloma. Copyright (c) 2018 Elsevier Ltd. All rights reserved.