Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma The CheckMate 143 Phase 3 Randomized Clinical Trial
Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma The CheckMate 143 Phase 3 Randomized Clinical Trial
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DOI：
10.1001/jamaoncol.2020.1024
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发表时间：
2020-07-01
期刊：
影响因子：
28.4
通讯作者：
Weller, Michael
中科院分区：
文献类型：
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作者：
Reardon, David A.;Brandes, Alba A.;Weller, Michael
胶质母细胞瘤的临床结果仍然很差。免疫检查点阻断治疗在许多癌症类型中显示出益处。据我们所知，数据从一个随机的3期临床试验评估程序性死亡-1（PD-1）抑制剂治疗胶质母细胞瘤还没有reported.Objective确定是否单药PD-1封锁nivolumab改善复发性胶质母细胞瘤患者的生存率相比，贝伐单抗。设计、设置和参与者在这项开放标签、随机、3期临床试验中，439例标准放疗和替莫唑胺治疗后首次复发的胶质母细胞瘤患者入选，其中369例随机分组。患者在2014年9月至2015年5月期间入组。截至数据截止日期2017年1月20日，中位随访时间为9.5个月。该研究包括57个多中心，多国临床sites.Interventions患者被随机1：1 nivolumab 3 mg/kg或贝伐单抗10 mg/kg，每2周，直到确认疾病进展，不可接受的毒性作用，或death.Main结局和措施的主要终点是总生存期（OS）。MGMT启动子在23.4%（43/184; nivolumab）和22.7%（42/185;贝伐珠单抗）中甲基化，在32.1%（59/184; nivolumab）和36.2%（67/185;贝伐珠单抗）中未甲基化，其余患者中未报告。在中位随访9.5个月时，两组的中位OS（mOS）相当：纳武利尤单抗，9.8个月（95%CI，8.2-11.8）;贝伐珠单抗，10.0个月（95%CI，9.0-11.8）; HR，1.04（95%CI，0.83-1.30）; P = 0.76。两组的12个月OS均为42%。贝伐珠单抗组的客观缓解率（23.1%; 95% CI，16.7%-30.5%）高于纳武利尤单抗组（7.8%; 95% CI，4.1%-13.3%）。两组之间3/4级治疗相关不良事件（TRAE）相似（纳武单抗，33/182 [18.1%];贝伐单抗，25/165 [15.2%]），没有意外的神经系统TRAE或TRAE引起的死亡。结论和相关性尽管在该随机临床试验中没有达到主要终点，在复发性胶质母细胞瘤的总体患者人群中，纳武单抗和贝伐珠单抗之间的mOS相当。nivolumab在胶质母细胞瘤患者中的安全性特征与其他肿瘤类型一致。
IMPORTANCE Clinical outcomes for glioblastoma remain poor. Treatment with immune checkpoint blockade has shown benefits in many cancer types. To our knowledge, data from a randomized phase 3 clinical trial evaluating a programmed death-1 (PD-1) inhibitor therapy for glioblastoma have not been reported.OBJECTIVE To determine whether single-agent PD-1 blockade with nivolumab improves survival in patients with recurrent glioblastoma compared with bevacizumab. Design, Setting, andPARTICIPANTS In this open-label, randomized, phase 3 clinical trial, 439 patients with glioblastoma at first recurrence following standard radiation and temozolomide therapy were enrolled, and 369 were randomized. Patients were enrolled between September 2014 and May 2015. The median follow-up was 9.5 months at data cutoff of January 20, 2017. The study included 57 multicenter, multinational clinical sites.INTERVENTIONS Patients were randomized 1:1 to nivolumab 3 mg/kg or bevacizumab 10 mg/kg every 2 weeks until confirmed disease progression, unacceptable toxic effects, or death.MAIN OUTCOMES AND MEASURES The primary end point was overall survival (OS).RESULTS A total of 369 patients were randomized to nivolumab (n = 184) or bevacizumab (n = 185). The MGMT promoter was methylated in 23.4% (43/184; nivolumab) and 22.7% (42/185; bevacizumab), unmethylated in 32.1% (59/184; nivolumab) and 36.2% (67/185; bevacizumab), and not reported in remaining patients. At median follow-up of 9.5 months, median OS (mOS) was comparable between groups: nivolumab, 9.8 months (95% CI, 8.2-11.8); bevacizumab, 10.0 months (95% CI, 9.0-11.8); HR, 1.04 (95% CI, 0.83-1.30); P = .76. The 12-month OS was 42% in both groups. The objective response rate was higher with bevacizumab (23.1%; 95% CI, 16.7%-30.5%) vs nivolumab (7.8%; 95% CI, 4.1%-13.3%). Grade 3/4 treatment-related adverse events (TRAEs) were similar between groups (nivolumab, 33/182 [18.1%]; bevacizumab, 25/165 [15.2%]), with no unexpected neurological TRAEs or deaths due to TRAEs.CONCLUSIONS AND RELEVANCE Although the primary end point was not met in this randomized clinical trial, mOS was comparable between nivolumab and bevacizumab in the overall patient population with recurrent glioblastoma. The safety profile of nivolumab in patients with glioblastoma was consistent with that in other tumor types.