DDDR-57. A brain-penetrant EGFR inhibitor overcomes EGFR variant heterogeneity in glioblastoma

Abstract The epidermal growth factor receptor (EGFR) is one of the most frequently altered genes in glioblastoma (GBM), yet therapeutic efforts have been limited by the heterogeneity of EGFR variants and poor blood–brain barrier permeability. We describe KTM-101, a reversible, highly selective EGFR inhibitor engineered for CNS delivery and broad activity against both amplified wild-type and extracellular domain EGFR mutants common to GBM. KTM-101 exhibited exceptionally high brain-to-plasma ratio across species (3.9-13) and effectively suppressed EGFR phosphorylation, downstream signaling, and tumor growth across diverse EGFR-altered patient-derived gliomasphere and orthotopic xenograft (PDOX) models at well tolerated exposures. Preliminary clinical evidence from a first-in-human phase I trial (NCT05222802) supports activity in a patient with recurrent, EGFR-altered GBM. In a large-scale, preclinical phase II-like trial across 30 distinct PDOX models, KTM-101 achieved an objective response rate (ORR) of 43% and extended median survival by 93% in EGFR-altered responsive models, with the greatest efficacy observed in newly diagnosed GBM. These findings position KTM-101 as a new brain-penetrant EGFR inhibitor with the potential to overcome longstanding challenges in treating EGFR-driven GBM and to enable precision-targeted therapy for this aggressive cancer.