de Melo Suely M, Elias Nunes da Silva Mauricio En, Torloni Maria Regina, Riera Rachel, De Cicco Kelly, Latorraca Carolina Oc, Pinto Ana Carolina Pereira Nunes
Departamento de Neurocirurgia, Escola Paulista de Medicina (EPM), Universidade Federal de Sao Paulo (UNIFESP), São Paulo, Brazil.
Neuro Oncologia, Hospital do Coração de São Paulo, São Paulo, Brazil.
Cochrane Database Syst Rev. 2025 Jan 8;1(1):CD012532. doi: 10.1002/14651858.CD012532.pub2.
Glioblastoma multiforme (GBM) is the most common and aggressive adult glioma (16-month median survival). Its immunosuppressive microenvironment limits the efficacy of immune checkpoint inhibitors (ICIs).
To assess the effects of the ICIs antibodies anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1) in treating adults with diffuse glioma.
We searched CENTRAL, MEDLINE, Embase, and clinical trials registers on 8 March 2024.
We included randomised controlled trials (RCTs) evaluating adults with diffuse glioma treated with anti-PD-1/PD-L1 compared to placebo or other therapies used alone or with other ICIs. Primary outcomes were overall survival (OS), progression-free survival (PFS), and serious adverse events (SAE). Secondary outcomes were overall response rate (ORR), quality of life (QoL), and less serious AEs.
We followed standard Cochrane methods.
We included seven RCTs evaluating anti-PD-1 treatment in recurrent (N = 4) and newly diagnosed (N = 3) grade 4 glioma participants. The analysis encompassed 1953 participants; sample sizes ranged from 35 to 716. Meta-analyses were not possible due to heterogeneity and the small number of studies. Most trials had high risk of bias. Nivolumab versus bevacizumab in people with recurrent GBM (1 trial, 369 participants) Nivolumab probably does not increase OS (hazard ratio (HR) 1.04, 95% confidence interval (CI) 0.83 to 1.30; 1.3% more, 95% CI 6.30 fewer to 7.80 more; 369 participants; moderate-certainty evidence) or PFS (HR 1.97, 95% CI 1.57 to 2.48; 16.40% more, 95% CI 12.40 more to 19.00 more; 369 participants; moderate-certainty evidence). The evidence for SAE is very uncertain (risk ratio (RR) 1.20, 95% CI 0.74 to 1.92; 347 participants). Nivolumab probably does not increase ORR (RR 0.34, 95% CI 0.18 to 0.63; 309 participants; moderate-certainty evidence), but may not increase less serious AEs (RR 1.03, 95% CI 0.96 to 1.10; 347 participants; low-certainty evidence). Nivolumab plus bevacizumab 10 mg/kg versus nivolumab plus bevacizumab 3 mg/kg in people with recurrent GBM (1 trial, 90 participants) Nivolumab plus bevacizumab 10 mg/kg may not increase OS (HR 1.39, 95% CI 0.86 to 2.25; 9.90% more, 95% CI 5.20 fewer to 18.80 more; 90 participants; low-certainty evidence). The evidence for PFS (HR 1.23, 95% CI 0.78 to 1.93; 5.80% more, 95% CI 8.20 fewer to 14.20 more; 90 participants) and SAE (RR 1.19, 95% CI 0.79 to 1.79; 90 participants) is very uncertain. Nivolumab may not increase less serious AEs (RR 1.02, 95% CI 0.96 to 1.09; low-certainty evidence; 90 participants). Pembrolizumab plus bevacizumab versus pembrolizumab in people with recurrent GBM (1 trial, 80 participants) The evidence for OS (HR 1.03, 95% CI 0.65 to 1.63; 0.30% more, 95% CI 7.60 fewer to 2.90 more; 80 participants), PFS (HR 0.97, 95% CI 0.61 to 1.54: 0.40% fewer, 95% CI 9.20 fewer to 2.80 more; 80 participants), SAE (RR 1.32, 95% CI 0.75 to 2.42; 80 participants), and ORR (RR 12.76, 95% CI 0.77 to 210.27; 80 participants) is very uncertain. Pembrolizumab plus bevacizumab may not increase less serious AEs (RR 1.04, 95% CI 0.96 to 1.13; 80 participants; low-certainty evidence). Neoadjuvant (before surgical resection) and adjuvant (after surgical resection) pembrolizumab versus adjuvant-only pembrolizumab in people with recurrent GBM (1 trial, 35 participants) The evidence for OS (HR 0.39, 95% CI 0.17 to 0.92; 25.20% fewer, 95% CI 37.10 fewer to 2.10 fewer; 35 participants), PFS (HR 0.43, 95% CI 0.20 to 0.91; 30.10% fewer, 95% CI 52.20 fewer to 3.60 fewer; 35 participants), and SAE (RR 1.00, 95% CI 0.31 to 3.28; 32 participants) is very uncertain. Nivolumab plus radiotherapy versus temozolomide plus radiotherapy in people with newly diagnosed unmethylated GBM (1 trial, 560 participants) Nivolumab plus radiotherapy probably does not increase OS (HR 1.31, 95% CI 1.09 to 1.58 months; 8.30% more, 95% CI 2.80 more to 12.90 more; 560 participants) and PFS (HR 1.38, 95% CI 1.15 to 1.65 months; 7.50% more, 95% CI 3.60 more to 10.30 more; 560 participants; moderate-certainty evidence). The evidence for SAE is very uncertain (RR 0.87, 95% CI 0.65 to 1.18; 553 participants). It may not increase ORR (RR 1.08, 95% CI 0.43 to 2.69; 560 participants; low-certainty evidence) and probably does not increase less serious AEs (RR 1.00, 95% CI 0.96 to 1.04; 560 participants; moderate-certainty evidence). The evidence for time to deterioration of QoL is very uncertain (HR 0.76, 95% CI 0.59 to 0.99; 560 participants). Nivolumab plus temozolomide plus radiotherapy versus placebo plus temozolomide plus radiotherapy in people with newly diagnosed methylated GBM (1 trial, 716 participants) Nivolumab plus temozolomide plus radiotherapy probably does not increase OS (HR 1.10, 95% CI 0.92 to 1.32; 3.50 more, 95% CI 3.80 fewer to 9.60 more; 716 participants) and PFS (HR 1.10, 95% CI 0.92 to 1.32; 3.00 more, 95% CI 3.50 fewer to 7.90 more; 716 participants), and probably increases SAE (RR 2.91, 95% CI 2.05 to 4.12; 709 participants; moderate-certainty evidence). It does not increase less serious AEs (RR 1.02, 95% CI 1.00 to 1.04; 709 participants; high-certainty evidence). Adjuvant nivolumab plus temozolomide versus temozolomide in older people with GBM (1 trial, 103 participants) Nivolumab plus temozolomide probably does not increase OS (HR 0.85, 95% CI 0.54 to 1.33; 3.10 fewer, 95% CI 15.80 fewer to 3.60 more; 103 participants; moderate-certainty evidence) and PFS (HR 0.77, 95% CI 0.49 to 1.19; 5.40 fewer, 95% CI 19.10 fewer to 2.40 more; 103 participants; moderate-certainty evidence). The evidence for SAE is very uncertain (RR 1.58, 95% CI 0.88 to 2.81; 103 participants). The evidence for QoL is very uncertain (results only reported graphically; 103 participants).
AUTHORS' CONCLUSIONS: In recurrent GBM, nivolumab alone probably has no benefit. Anti-PD1 plus bevacizumab may also be ineffective based on low- to very low-certainty evidence. Neoadjuvant plus adjuvant pembrolizumab may improve OS and PFS, but this was based on only one small trial and very low-certainty evidence. In newly diagnosed GBM, nivolumab plus radiotherapy in unmethylated and plus radiotherapy plus temozolomide in methylated GBM probably has no benefit. In older participants, adjuvant nivolumab probably offers no benefit.
多形性胶质母细胞瘤（GBM）是最常见且侵袭性最强的成人胶质瘤（中位生存期为16个月）。其免疫抑制微环境限制了免疫检查点抑制剂（ICI）的疗效。
评估ICI抗体抗程序性细胞死亡蛋白1（抗PD-1）和抗程序性细胞死亡配体1（抗PD-L1）治疗成人弥漫性胶质瘤的效果。
我们于2024年3月8日检索了Cochrane中心对照试验注册库、MEDLINE、Embase及临床试验注册库。
我们纳入了评估抗PD-1/PD-L1治疗成人弥漫性胶质瘤的随机对照试验（RCT），并与安慰剂或单独使用或与其他ICI联合使用的其他疗法进行比较。主要结局为总生存期（OS）、无进展生存期（PFS）和严重不良事件（SAE）。次要结局为总缓解率（ORR）、生活质量（QoL）和不太严重的不良事件。
我们遵循标准的Cochrane方法。
我们纳入了7项RCT，评估复发性（n = 4）和新诊断（n = 3）的4级胶质瘤患者接受抗PD-1治疗的情况。分析涵盖1953名参与者；样本量从35到716不等。由于异质性和研究数量较少，无法进行Meta分析。大多数试验存在高偏倚风险。复发性GBM患者中纳武单抗与贝伐单抗比较（1项试验，369名参与者）纳武单抗可能不会增加OS（风险比（HR）1.04，95%置信区间（CI）0.83至1.30；多1.3%，95%CI少6.30至多7.80；369名参与者；中等确定性证据）或PFS（HR 1.97，95%CI 1.57至2.48；多16.40%，95%CI多12.40至多19.00；369名参与者；中等确定性证据）。SAE的证据非常不确定（风险比（RR）1.20，95%CI 0.74至1.92；347名参与者）。纳武单抗可能不会增加ORR（RR 0.34，95%CI 0.18至0.63；309名参与者；中等确定性证据），但可能不会增加不太严重的不良事件（RR 1.03，95%CI 0.96至1.10；347名参与者；低确定性证据）。复发性GBM患者中纳武单抗加10mg/kg贝伐单抗与纳武单抗加3mg/kg贝伐单抗比较（1项试验，90名参与者）纳武单抗加10mg/kg贝伐单抗可能不会增加OS（HR 1.39，95%CI 0.86至2.25；多9.90%，95%CI少5.20至多18.80；90名参与者；低确定性证据）。PFS（HR 1.23，95%CI 0.78至1.93；多5.80%，95%CI少8.20至多14.20；90名参与者）和SAE（RR 1.19，95%CI 0.79至1.79；90名参与者）的证据非常不确定。纳武单抗可能不会增加不太严重的不良事件（RR 1.02，95%CI 0.96至1.09；低确定性证据；90名参与者）。复发性GBM患者中帕博利珠单抗加贝伐单抗与帕博利珠单抗比较（1项试验，80名参与者）OS（HR 1.03，95%CI 0.65至1.63；多0.30%，95%CI少7.60至多2.90；80名参与者）、PFS（HR
