有证据表明，通过 ERK1/2 磷酸化 (p-ERK) 测量的 MAPK 通路激活可预测接受抗 PD-1 治疗的复发性胶质母细胞瘤患者的总生存期 (OS)。我们的目的是在独立队列中验证这些发现。在一项针对复发性胶质母细胞瘤和高级别胶质瘤的 24 名患者临床试验中，我们检查了 p-ERK 水平与总生存 (OS) 之间的联系。患者接受静脉注射纳武单抗，然后进行最大安全切除，并单独或与纳武单抗联合脑内注射伊匹单抗。然后每两周给予一次辅助纳武单抗最多五次（NCT03233152）。使用 REMARK 标准，我们对 p-ERK 量化和统计评估进行了独立分析。其他比较分析包括之前的队列，总共 65 名患者。采用 Cox 比例风险模型和荟萃分析来评估 p-ERK 作为免疫治疗后的预测生物标志物。与之前的研究相比，观察到 p-ERK 细胞密度中位数较低，这可能是由于组织处理差异所致。尽管如此，高 p-ERK 与延长 OS 相关，特别是在 IDH 野生型胶质母细胞瘤中 (P=0.036)。高 p-ERK 患者和低 p-ERK 患者的中位 OS 分别为 55.6 周和 30 周。多变量分析强化了 p-ERK 在生存预测中的重要性（P=0.011）。三个队列 (n=65) 的荟萃分析支持肿瘤 p-ERK 水平升高的生存获益 (P=0.0424)。这项研究强化了 p-ERK 作为免疫检查点阻断的胶质母细胞瘤患者 OS 预测生物标志物的作用。未来的研究应侧重于前瞻性试验的进一步验证以及影响 p-ERK 定量的分析前变量的标准化。

Evidence suggests that MAPK pathway activation, as measured by ERK1/2 phosphorylation (p-ERK), predicts overall survival (OS) in recurrent glioblastoma patients receiving anti-PD-1 therapy. We aimed to validate these findings in independent cohorts.In a 24-patient clinical trial on recurrent glioblastoma and high-grade gliomas, we examined the link between p-ERK levels and overall survival (OS). Patients received intravenous nivolumab, followed by maximal safe resection and an intracerebral injection of either ipilimumab alone or combined with nivolumab. Bi-weekly adjuvant nivolumab was then administered up to five times (NCT03233152). Using REMARK criteria, we conducted independent analyses for p-ERK quantification and statistical evaluations. Additional comparative analysis included prior cohorts, totaling 65 patients. Cox proportional hazards models and meta-analysis were employed to assess p-ERK as a predictive biomarker post-immunotherapy.Lower median p-ERK+ cell density was observed compared to prior studies, likely due to tissue handling variances. Nonetheless, high p-ERK was associated with prolonged OS, particularly in IDH wild-type glioblastomas (P=0.036). Median OS for high and low p-ERK patients were 55.6 and 30 weeks, respectively. Multivariable analysis reinforced p-ERK's significance in survival prediction (P=0.011). Meta-analysis across three cohorts (n=65) supported the survival benefit of elevated tumor p-ERK levels (P=0.0424).This study strengthens the role of p-ERK as a predictive biomarker for OS in glioblastoma patients on immune checkpoint blockade. Future research should focus on further validation in prospective trials and the standardization of preanalytical variables influencing p-ERK quantification.