DDDR-43. ERAS-801 IS A SELECTIVE BRAIN-PENETRANT EGFR INHIBITOR WITH IMPROVED ACTIVITY AGAINST EGFR EXTRACELLULAR DOMAIN-MUTANT GLIOBLASTOMA

Abstract Epidermal growth factor receptor (EGFR) is a driver of nearly 50% of glioblastoma (GBM), yet EGFR inhibitors have failed in GBM (e.g., erlotinib, lapatinib, neratinib, gefitinib, and afatinib) due to poor CNS penetration and/or an inability to inhibit EGFR in its wildtype and extracellular domain (ECD) mutated forms (e.g., EGFRvIII). Here we describe ERAS-801, a reversible and selective EGFR tyrosine kinase inhibitor with unique binding properties that enable potent activity for amplified and ECD mutant EGFR. ERAS-801 demonstrated the highest nonclinical CNS penetration out of all tested EGFR inhibitor comparators. Accordingly, relative to other EGFR inhibitors tested in GBM trials (e.g., erlotinib, lapatinib, and osimertinib), ERAS-801 showed superior survival benefit in EGFR altered orthotopic PDX models. Finally, further characterization of ERAS-801 in a preclinical trial of glioma orthotopic PDX models that capture the molecular heterogeneity of GBM, ERAS-801 demonstrated a significant survival benefit at a 25 mg/kg QD dose in the vast majority of EGFR-driven orthotopic GBM PDX models, with FDG-PET imaging serving as a non-invasive biomarker of response. Based on these nonclinical data, ERAS-801 is currently under clinical investigation for GBM.