ERK1/2 Phosphorylation Predicts Survival in Recurrent Glioblastoma Following Intracerebral and Adjuvant PD-1/CTLA-4 Immunotherapy: A REMARK-guided Analysis

Víctor A. Arrieta, Johnny Duerinck, Kirsten B. Burdett, Karl J. Habashy, Wietse Geens, Andrew Gould, Julia K. Schwarze, Crismita Dmello, Kwang Soo Kim, Ruth Saganty, Li Chen, Alberto Moscona, Matthew McCord, Catalina Lee-Chang, Craig M. Horbinski, Hui Zhang, Roger Stupp, Bart Neyns, Adam M. Sonabend*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Evidence suggests that MAPK pathway activation, as measured by ERK1/2 phosphorylation (p-ERK), predicts overall survival (OS) in patients with recurrent glioblastoma receiving anti-PD-1 therapy. We aimed to validate these findings in independent cohorts. Experimental Design: In a 24-patient clinical trial on recurrent glioblastoma and high-grade gliomas, we examined the link between p-ERK levels and OS. Patients received intravenous nivolumab, followed by maximal safe resection and an intracerebral injection of either ipilimumab alone or combined with nivolumab. Biweekly adjuvant nivolumab was then administered up to five times (NCT03233152). Using REporting recommendations for tumor MARKER prognostic studies (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 after immunotherapy. Results: Lower median p-ERKþ cell density was observed compared with prior studies, likely due to variable tissue processing across cohorts. Nonetheless, high p-ERK was associated with prolonged OS, particularly in isocitrate dehydrogenase wild-type glioblastomas (P ¼ 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 ¼ 0.011). Upon p-ERK normalization across cohorts (n ¼ 65), meta-analysis supported the survival benefit of elevated tumor p-ERK levels (P ¼ 0.0424). Conclusions: This study strengthens the role of p-ERK as a predictive biomarker for OS in patients with glioblastoma on immune checkpoint blockade. Future research should focus on further validation in prospective trials and the standardization of preanalytical variables influencing p-ERK quantification.

Original languageEnglish (US)
Pages (from-to)379-388
Number of pages10
JournalClinical Cancer Research
Volume30
Issue number2
DOIs
StatePublished - Jan 15 2024

ASJC Scopus subject areas

  • General Medicine

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