Resistance of recurrent epidermal growth factor receptor-altered glioblastoma to anti-epidermal growth factor receptor targeted therapy with osimertinib.

Glioblastoma (GBM) is a highly aggressive brain tumor with limited treatment options and poor prognosis. Epidermal growth factor receptor (EGFR) alterations, including amplifications, mutations, and fusions, are prevalent in GBM and represent potential therapeutic targets. Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), has demonstrated efficacy in EGFR-mutated non-small cell lung cancer and central nervous system metastases. However, its efficacy in GBM remains uncertain. We present 2 cases of recurrent GBM harboring distinct EGFR alterations treated with osimertinib. Both patients, despite showing EGFR amplification or activating mutations (G719D), experienced rapid disease progression and clinical deterioration during treatment. These findings highlight the resistance of GBM to osimertinib, possibly due to tumor heterogeneity, subclonal variation, or intrinsic mechanisms linked to EGFR amplification and redundant oncogenic pathways. Our observations align with prior trials of EGFR-TKIs in GBM, which have shown limited benefit. These cases underscore the complexity of targeting EGFR in GBM and the need for advanced therapeutic approaches, including next-generation EGFR inhibitors and antibody-drug conjugates, to overcome resistance. Further studies are crucial to optimize EGFR-targeted therapies in GBM.