494 Evaluating ERK1 2 Phosphorylation As a Predictive Biomarker for Survival in Recurrent Glioblastoma Patients: A REMARK Criteria-guided Analysis of a Clinical Trial Cohort Treated with Intracerebral PD-1 and CTLA-4 Blockade

INTRODUCTION: Glioblastoma patients exhibit variable clinical responses to anti-PD-1 immunotherapy. Our previous work identified ERK1/2 phosphorylation (p-ERK) in pre-treatment tumor samples as a predictive biomarker of overall survival in two independent cohorts of recurrent glioblastoma patients undergoing adjuvant anti-PD-1 therapy (Arrieta et al, Nat Cancer, 2021). This biomarker, however, has not yet been explored with alternative immune checkpoint blockade strategies nor assessed using REMARK criteria. METHODS: Adhering to REMARK criteria for biomarker validation, we investigated p-ERK as a predictor of survival in 24 evaluable recurrent glioblastoma patients from a clinical trial (NCT03233152; Duerinck J, et al, JITC, 2021). Patients underwent intracerebral administration of immune checkpoint inhibitors within a phase I clinical trial, receiving either ipilimumab (10 mg), or a combination of ipilimumab (5 mg) and nivolumab (10 mg), followed by postsurgical intravenous nivolumab (10 mg). We quantified p-ERK+ cell density in tumor regions and conducted a double-blinded statistical analysis of p-ERK’s association with survival outcomes, performed by an independent statistical team. RESULTS: Although analysis of the entire cohort revealed no statistically significant survival difference between patients with high and low p-ERK tumors (p = 0.29), a focused examination of wild-type IDH GBM patients demonstrated a significantly prolonged survival for those with high p-ERK tumors (median survival = 55.6 weeks, 95% CI 33.86-NA) compared to those with low p-ERK tumors (median OS of 30 weeks, 95% CI 16.14-NA; p = 0.036). CONCLUSIONS: Despite the limited sample size, this study highlights the promising predictive potential of p-ERK as a biomarker in a third independent prospective glioblastoma cohort treated with a novel immune checkpoint blockade administration approach, emphasizing the need for further investigation and validation in larger cohorts.