Background

Enasidenib is an oral inhibitor of mutant isocitrate dehydrogenase-2 (IDH2) proteins. We evaluated the safety and activity of enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia ineligible for intensive chemotherapy.

Methods

This open-label, phase 1b/2 trial was done at 43 clinical sites in 12 countries (the USA, Germany, Canada, the UK, France, Spain, Australia, Italy, the Netherlands, Portugal, Switzerland, and South Korea). Eligible patients were aged 18 years or older and had newly diagnosed, mutant-IDH2 acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0–2. In the phase 1b dose-finding portion, patients received oral enasidenib 100 mg/day or 200 mg/day in continuous 28-day cycles, plus subcutaneous azacitidine 75 mg/m² per day for 7 days of each cycle. In phase 2, patients were randomly assigned (2:1) via an interactive web response system to enasidenib plus azacitidine or azacitidine-only, stratified by acute myeloid leukaemia subtype (de novo or secondary). The primary endpoint in the phase 2 portion was the overall response rate in the intention-to-treat population at a prespecified interim analysis (Aug 20, 2019) when all patients had at least 1 year of follow-up. Safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT02677922, and is ongoing.

Findings

Between June 3, 2016, and Aug 2, 2018, 322 patients were screened and 107 patients with mutant-IDH2 acute myeloid leukaemia were enrolled. At data cutoff for the interim analysis, 24 patients (including two from the phase 1 portion) were still receiving their assigned treatment. Six patients were enrolled in the phase 1b dose-finding portion of the trial and received enasidenib 100 mg (n=3) or 200 mg (n=3) in combination with azacitidine. No dose-limiting toxicities occurred and the enasidenib 100 mg dose was selected for phase 2. In phase 2, 101 patients were randomly assigned to enasidenib plus azacitidine (n=68) or azacitidine only (n=33). Median age was 75 years (IQR 71–78). 50 (74%; 95% CI 61–84) patients in the enasidenib plus azacitidine combination group and 12 (36%; 20–55) patients in the azacitidine monotherapy group achieved an overall response (odds ratio 4·9 [95% CI 2·0–11·9]; p=0·0003). Common treatment-related grade 3 or 4 adverse events with enasidenib plus azacitidine were thrombocytopenia (25 [37%] of 68 vs six [19%] of 32 in the azacitidine-only group), neutropenia (25 [37%] vs eight [25%]), anaemia (13 [19%] vs seven [22%]), and febrile neutropenia (11 [16%] vs five [16%]). Serious treatment-related adverse events were reported in 29 (43%) patients in the combination group and 14 (44%) patients in the azacitidine-only group; serious treatment-related adverse events occurring in more than 5% of patients in either group were febrile neutropenia (nine [13%] in the combination group vs five [16%] in the azacitidine-only group), differentiation syndrome (seven [10%] vs none), and pneumonia (three [4%] vs two [6%]). No treatment-related deaths were reported.

Interpretation

Combination enasidenib plus azacitidine was well tolerated and significantly improved overall response rates compared with azacitidine monotherapy, suggesting that this regimen can improve outcomes for patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia.

Funding

Bristol Myers Squibb.

中文翻译：

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Enasidenib 加阿扎胞苷与单用阿扎胞苷治疗新诊断的突变 IDH2 急性髓细胞白血病 (AG221-AML-005)：单组 1b 期和随机 2 期试验

背景

Enasidenib 是一种突变异柠檬酸脱氢酶 2 (IDH2) 蛋白的口服抑制剂。我们评估了 enasidenib 加阿扎胞苷与单用阿扎胞苷相比，在新诊断的、不适合强化化疗的突变IDH2急性髓细胞白血病患者中的安全性和活性。

方法

这项开放标签的 1b/2 期试验在 12 个国家（美国、德国、加拿大、英国、法国、西班牙、澳大利亚、意大利、荷兰、葡萄牙、瑞士和韩国）的 43 个临床中心进行。符合条件的患者年龄在 18 岁或以上，并且患有新诊断的突变型IDH2急性髓细胞白血病，并且东部肿瘤协作组的体能状态为 0-2。在 1b 期剂量寻找部分，患者接受口服 enasidenib 100 mg/天或 200 mg/天连续 28 天周期，加上皮下注射阿扎胞苷 75 mg/m ²每个周期的 7 天，每天一次。在第 2 阶段，患者通过交互式网络响应系统被随机分配 (2:1) 到 enasidenib 加阿扎胞苷或仅阿扎胞苷，按急性髓细胞白血病亚型（从头或继发）分层。第 2 期部分的主要终点是在预先指定的中期分析（2019 年 8 月 20 日）中意向治疗人群的总体反应率，当时所有患者都进行了至少 1 年的随访。在接受至少一剂研究药物的所有患者中评估安全性。该试验已在 ClinicalTrials.gov 注册，NCT02677922，并且正在进行中。

发现

2016 年 6 月 3 日至 2018 年 8 月 2 日期间，筛选了 322 名患者和 107 名突变型IDH2患者入组急性髓性白血病。在中期分析的数据截止时，24 名患者（包括 2 名来自 1 期部分）仍在接受指定的治疗。6 名患者参加了试验的 1b 期剂量寻找部分，并接受了 enasidenib 100 mg（n=3）或 200 mg（n=3）联合阿扎胞苷治疗。没有发生剂量限制性毒性，并且选择 enasidenib 100 mg 剂量用于第 2 阶段。在第 2 阶段，101 名患者被随机分配到 enasidenib 加阿扎胞苷（n = 68）或仅阿扎胞苷（n = 33）。中位年龄为 75 岁（IQR 71-78）。enasidenib 加阿扎胞苷联合治疗组有 50 名（74%；95% CI 61-84）名患者和阿扎胞苷单药治疗组有 12 名（36%；20-55）名患者获得了总体缓解（优势比 4·9 [95% CI 2·0-11·9]；p=0·0003)。阿扎胞苷组 32 人中有 6 人 [19%]）、中性粒细胞减少（25 [37%]对8 [25%]）、贫血（13 [19%]对7 [22%]）和发热性中性粒细胞减少（ 11 [16%]对5 [16%])。联合组 29 例（43%）患者和阿扎胞苷单独组 14 例（44%）患者报告了严重的治疗相关不良事件；两组中超过 5% 的患者发生严重的治疗相关不良事件包括发热性中性粒细胞减少症（联合组 9 例 [13%]和阿扎胞苷单独组 5 例 [16%]）、分化综合征（7 例 [10 %]对无）和肺炎（三个 [4%]对两个 [6%]）。没有报告与治疗相关的死亡。

解释

与阿扎胞苷单药治疗相比，enasidenib 联合阿扎胞苷具有良好的耐受性并显着提高了总体反应率，这表明该方案可以改善新诊断的突变IDH2急性髓性白血病患者的预后。

资金

百时美施贵宝。