以前在台湾进行的一项1期剂量递增研究表明，CAN008（asunercept）与标准的同步化疗放疗（CCRT）相结合治疗改善了新诊断的胶质母细胞性脑瘤（GBM）患者的无进展生存期（PFS）。本研究评估了CAN008在提高总生存期（OS）方面的疗效，并确定了与治疗反应相关的遗传变异。我们将评估9名可评估的CAN008队列患者（6人接受高剂量，3人接受低剂量）5年随访的OS与台湾历史性GBM队列164名新诊断患者对比。通过全外显子测序和比较反应组间变异差异，确定与CAN008治疗反应相关的遗传变异。使用CAN008队列和TCGA-GBM数据集，分析患者生存、肿瘤突变负荷（TMB）和遗传变异之间的关联。高剂量CAN008患者2年和5年的OS分别为83%和67%，而历史GBM队列分别为40.1%和8.8%。高剂量CAN008队列的OS较历史GBM队列更好（未达到中位生存期），差异有统计学意义（中位OS：20个月；p=0.0103）。根据PFS将5名高剂量CAN008患者分为良好反应组和差劣反应组。良好反应患者观察到更高的变异计数和TMB，而新诊断的TCGA-GBM数据集中TMB与患者生存之间没有显著的关联，表明TMB可能调节患者对CAN008的反应。与单独的标准治疗相比，CAN008与标准CCRT联合治疗延长了新诊断GBM患者的PFS和OS。较高的治疗疗效与较高的TMB相关。版权所有©2023作者。由Elsevier B.V.出版。保留所有权利。

A previous phase 1 dose-escalation study in Taiwan indicated CAN008 (asunercept) with standard concurrent chemoradiotherapy (CCRT) improved progression-free survival (PFS) in newly diagnosed glioblastoma (GBM) patients. This study evaluates the efficacy of CAN008 in promoting overall survival (OS) and identifies genetic alterations associated with treatment responses.We compared OS of 5-year follow-ups from 9 evaluable CAN008 cohort patients (6 received high-dose and 3 received low-dose) to a historical Taiwanese GBM cohort with 164 newly diagnosed patients. CAN008 treatment response-associated genetic alterations were identified by whole-exome sequencing and comparing variant differences between response groups. Associations among patient survival, tumor mutational burden (TMB), and genetic alterations were analyzed using CAN008 cohort and TCGA-GBM dataset.OS for high-dose CAN008 patients at 2 and 5 years was 83% and 67%, respectively, and 40.1% and 8.8% for the historical GBM cohort, respectively. Better OS was observed in the high-dose CAN008 cohort (without reaching the median survival) than the historical GBM cohort (median OS: 20 months; p=0.0103). Five high-dose CAN008 patients were divided into good and poor response groups based on their PFS. A higher variant count and TMB were observed in good response patients, whereas no significant association was observed between TMB and patient survival in the newly diagnosed TCGA-GBM dataset, suggesting TMB may modulate patient CAN008 response.CAN008 combined with standard CCRT treatment prolonged the PFS and OS of newly diagnosed GBM patients compared to standard therapy alone. Higher treatment efficacy was associated with higher TMB.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.