Predictive value of EGFR amplification and EGFRvIII mutation in EGFR-targeted therapy for recurrent glioblastoma: a systematic review

Abstract Introduction Glioblastoma (GBM) is the most aggressive and biologically heterogeneous tumor of the central nervous system, associated with dismal prognosis and frequent recurrence. Amplification of the epidermal growth factor receptor (EGFR) and EGFRvIII mutation are common alterations, yet their prognostic significance remains unclear. This systematic review evaluated whether clinical evidence supports a predictive association between EGFR amplification or EGFRvIII mutation and response to EGFR-targeted therapy in adults with recurrent GBM. Methods PubMed, Embase and the Cochrane Library were searched (2010–2025) for studies of adults with recurrent GBM treated with EGFR-targeted therapies, with outcomes stratified by EGFR amplification and/or EGFRvIII. Screening, data extraction and risk-of-bias assessment were performed independently. Results Twelve studies (565 patients) met inclusion criteria. EGFR amplification was assessed in 11 studies and EGFRvIII in six using FISH, qPCR, RT-PCR, or NGS. Median overall survival ranged from 5.7 to 10.3 months and progression-free survival from 1.7 to 6.0 months, with no consistent survival benefit observed. Conclusion EGFR amplification and EGFRvIII mutation have not demonstrated reliable predictive value for EGFR-targeted therapy in recurrent GBM. The available evidence is largely derived from heterogeneous, single-arm studies, limiting robust assessment of biomarker specific treatment response and therefore these alterations are not recommended to be used to guide off-trial treatment decisions in recurrent GBM. Protocol Registration: www.crd.york.ac.uk/prospero identifier is CRD420251071466.