Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial
Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial
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DOI：
10.1016/s1470-2045(17)30517-x
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发表时间：
2017-10-01
期刊：
影响因子：
51.1
通讯作者：
Sampson, John H.
中科院分区：
文献类型：
--
作者：
Weller, Michael;Butowski, Nicholas;Sampson, John H.
背景Rindopepimut（也称为CDX-110），一种靶向EGFR缺失突变EGFRVIII的疫苗，由EGFRVIII特异性肽组成，该肽结合到钥匙孔lim limpet limpet Haemocyanin。在IV ACT研究中，我们旨在评估在标准化学疗法中添加皮皮膜的添加能够改善EGFRVIII阳性胶质母细胞瘤的患者的生存。来自22个国家的165个医院的胶质母细胞瘤以上的18岁及以上。符合条件的患者已新诊断出胶质母细胞瘤证实可以通过中央分析表达EGFRVIII，并接受了最大的手术切除和标准化学辐射的完成而无需进展。患者由欧洲组织进行癌症递归分区分析类别，MGMT启动子甲基化和地理区域的研究和治疗，以及随机分配的（1：1），具有预先指定的随机化序列（四个块大小），以接收Rindopepimut（500 MU（500 MU） G与150 Mu G GM-CSF混合）或对照（100 Mu G钥匙孔的lime蛋白）通过每月皮内注射直至进展或不耐受，与标准口服替莫唑胺（150-200 mg/m（2）持续28天的28天），持续6-12个周期或更长的循环。患者，研究人员和试验资助者被掩盖进行治疗分配。主要终点是在最小残留疾病的患者中的总生存率（MRD；通过中央审查增强化学后肿瘤<2 cm（2），通过改良的治疗意图进行了分析。该试验已在Clinicaltrials.gov中注册，编号NCT01480479。招募了2012年4月12日至2014年12月15日之间的发现，招募了745例患者（405例MRD，338例，有明显的残留疾病[SRD]和两种不可不可及的），并随机分配了。到Rindopepimut和Temozolomide（n = 371）或对照和替莫唑胺（n = 374）。在预先计划的临时分析后，该研究因徒劳而终止。在最终分析中，MRD患者的总生存期没有显着差异：中位总生存期为20。 1个月（95％CI18。5-22。1）在Rindopepimut组中与20。对照组的0个月（18。1-21。9）（HR 1。01，95％CI0。79-1。30; P =0。93）。在对照组中，在Rindopepimut组中，所有369例接受治疗的患者的最常见的3-4级不良事件是：血小板减少症（32 [9％] vs 23 [6％]），疲劳（6 [2％]） vs 19 [5％]），脑水肿（八个[2％] vs 11 [3％]），癫痫发作（九[2％] vs八[2％]）和头痛（六[2％] vs 10 [3％]）。严重的不良事件包括癫痫发作（18 [5％] vs 22 [6％]）和脑水肿（7 [2％] vs 12 [3％]）。该研究中的16例死亡是由不良事件（Rindopepimut组的9个[4％]，对照组中的7个[3％]引起的，其中64岁的男性患者在11个肺部栓塞造成。几个月的治疗方法被评估为可能与Rindopepimut有关。解释Rindopepimut并未增加新诊断的胶质母细胞瘤患者的存活率。可能需要使用包括皮皮膜的组合方法来显示免疫疗法在胶质母细胞瘤中的功效。
Background Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma.Methods In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 mu g admixed with 150 mu g GM-CSF) or control (100 mu g keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150-200 mg/m(2) for 5 of 28 days) for 6-12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour < 2 cm(2) post-chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479.Findings Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease [SRD], and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20 . 1 months (95% CI 18 . 5-22 . 1) in the rindopepimut group versus 20 . 0 months (18 . 1-21 . 9) in the control group (HR 1 . 01, 95% CI 0 . 79-1 . 30; p=0 . 93). The most common grade 3-4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache (six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] in the control group), of which one-a pulmonary embolism in a 64-year-old male patient after 11 months of treatment-was assessed as potentially related to rindopepimut.Interpretation Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma.