Evaluation of Regorafenib in Newly Diagnosed and Recurrent Glioblastoma: GBM AGILE Phase II/III Bayesian Randomized Platform Trial.

Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm.

多激酶抑制剂瑞戈非尼在 II 期 REGOMA 试验中显示出对复发性（RD）胶质母细胞瘤的总生存（OS）益处，并作为首个研究性治疗组进入 GBM AGILE。

Methods

Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma.

GBM AGILE研究中，接受瑞格非尼治疗的患者亚型包括新诊断的未甲基化（NDU）和复发性（RD）胶质母细胞瘤。

Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD).

预先定义的亚型集合，或称为治疗组特征，包括NDU、RD和所有（NDU + RD）。

As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm.

作为GBM AGILE研究中的首个研究组，瑞格非尼被随机均等地分配到对照组。

Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD).

对照组的治疗方案为替莫唑胺加放疗（针对新诊断的患者）或洛莫司汀（针对复发/难治性患者）。

Efficacy was assessed by OS hazard ratio(HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%.

疗效通过总生存（OS）风险比（HR）、治疗组/对照组进行评估，并在贝叶斯概率（HR <1.00）≥98%时显示有益效果。

Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment.

每月进行有限疗效分析，当所有标志物的贝叶斯预测能力<25%时，确定停止招募。

Follow-up continued for 12 months after accrual stopped.

随访在停止入组后继续进行了12个月。

Results

When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy.

当所有预定义的标志物对瑞戈非尼的预测能力<25%时，由于疗效有限，停止了入组。

The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma.

最终分析未显示RD和NDU胶质母细胞瘤中瑞戈非尼组的总生存期有所改善。

Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all).

中位风险比为1.05（NDU）、1.07（RD）和1.07（全部），最终获益概率（风险比<1.00）为0.421（NDU）、0.312（RD）和0.296（全部）。

Regorafenib was associated with increased toxicity relative to control.

与对照组相比，雷戈非尼与增加的毒性相关。

Conclusions

GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities.

GBM AGILE研究未显示雷戈非尼在RD（洛莫司汀）或NDU（替莫唑胺+放疗）胶质母细胞瘤中优于对照组，但引起了增加的毒性。

Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.

雷戈非尼已被从国家综合癌症网络指南中移除，不再作为RD的治疗选择。