Dual Immune Check Point Blockade in MGMT-Unmethylated Newly Diagnosed Glioblastoma: NRG Oncology BN007, a Randomized Phase II/III Clinical Trial.

NRG Oncology BN002 (phase I) demonstrated safety and suggested efficacy of ipilimumab (ipi) with nivolumab (nivo) in newly diagnosed glioblastoma, leading to this phase II/III trial.

NRG Oncology BN002（I期）试验表明，伊匹木单抗（ipi）与纳武利尤单抗（nivo）联合使用在新诊断的胶质母细胞瘤中显示出安全性和一定的疗效，从而引发了这项II/III期试验。

Methods

Adults with newly diagnosed uMGMT glioblastoma and Karnofsky performance status (KPS) ≥70 were randomly assigned to radiotherapy with either immunotherapy (ipi and nivo) or temozolomide (TMZ), stratified by recursive partitioning analysis (RPA) class and intention to use tumor treating fields.

新诊断为uMGMT阳性的成人胶质母细胞瘤患者，且Karnofsky功能状态（KPS）≥70，被随机分配接受放射治疗联合免疫治疗（ipi和nivo）或替莫唑胺（TMZ），按递归分割分析（RPA）类别和使用肿瘤治疗电场的意向进行分层。

With 95% power to detect a hazard ratio(HR) ≤0.58 for progression-free survival(PFS) at a one-sided significance level (P) of .15, superior PFS with immunotherapy in phase II would lead to phase III overall survival(OS) testing.

在单侧显著性水平（P）为0.15的情况下，具有95%的把握度检测到无进展生存（PFS）的风险比（HR）≤0.58，如果免疫治疗在II期显示出优越的PFS，则将进行III期总生存（OS）测试。

Corticosteroids were disallowed when starting immunotherapy.

在开始免疫治疗时禁止使用皮质类固醇。

Diagnosis, biomarkers, and PFS were centrally assessed.

诊断、生物标志物和无进展生存期（PFS）由中心进行评估。

Results

One hundred fifty-nine participants were randomly assigned (79 immunotherapy and 80 TMZ).

159名参与者被随机分配（79名接受免疫治疗，80名接受替莫唑胺治疗）。

Arms were well balanced for age (median 60 years, range, 28-79), sex (male n = 105, 66%), KPS (90-100 n = 97, 61%), resection extent (gross total, n = 103, 65%), and RPA class (III, n = 16, 10%; IV, n = 116, 73%; V, n = 27, 17%).

各组在年龄（中位数60岁，范围28-79岁）、性别（男性105名，占66%）、KPS评分（90-100分的有97名，占61%）、切除范围（全切除的有103名，占65%）以及RPA分级（III级16名，占10%；IV级116名，占73%；V级27名，占17%）方面均保持均衡。

A preplanned analysis of phase II data conducted after 100 centrally determined PFS events showed no significant PFS improvement for ipi and nivo versus TMZ (median 7.7 months v 8.5 months, HR, 1.47 [70% CI, 1.19 to 1.83]; one-sided P = .96 [95% CI, 0.98 to 2.2]).

在100个中心确定的无进展生存（PFS）事件后进行的II期数据的事先计划分析显示，伊匹木单抗和纳武利尤单抗与替莫唑胺相比，无显著的PFS改善（中位PFS分别为7.7个月和8.5个月，风险比（HR）为1.47 [70%置信区间（CI），1.19至1.83]；单侧P值为.96 [95% CI，0.98至2.2]）。

OS is immature (>50% alive) but with no observed difference between arms (median approximately 13 months each, HR, 0.95 [95% CI, 0.61 to 1.49]; P = .36).

总生存（OS）数据尚不成熟（>50%存活），但两组之间未观察到差异（中位OS均为约13个月，风险比（HR）为0.95 [95% CI，0.61至1.49]；P值为.36）。

Conclusions

Ipi and nivo did not improve PFS among patients with newly diagnosed uMGMT glioblastoma versus TMZ.

伊匹木单抗和纳武利尤单抗并未改善新诊断的uMGMT胶质母细胞瘤患者的无进展生存期（PFS），与替莫唑胺（TMZ）相比。

Accrual closed permanently; the trial will not proceed to phase III.

该试验的招募已永久关闭；试验将不会进入第三阶段。

No new safety signals were identified.

未发现新的安全信号。

Molecular correlative analyses and survival follow-up are ongoing.

分子相关性分析和生存随访正在进行中。