Early Phase 1 avutometinib dual RAF/MEK inhibitor + defactinib FAK inhibitor in newly diagnosed high-grade glioma

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins is running an early-phase, open-label feasibility and safety study testing avutometinib (VS-6766), a dual RAF/MEK pathway inhibitor, plus defactinib (VS-6063), a focal adhesion kinase inhibitor, before radiation in newly diagnosed high-grade glioma with measurable residual enhancing disease after surgery. Patients first receive one 4-week cycle of the targeted combination before radiation; those subsequently confirmed to have MGMT-unmethylated glioblastoma can continue avutometinib + defactinib for two additional cycles given concurrently with approximately 6 weeks of radiation, without temozolomide. Co-primary endpoints focus on whether patients can complete the pre-radiation cycle without delaying radiation beyond the protocol window and whether the regimen is tolerable across both treatment stages; radiographic response after the initial cycle is assessed by RANO 2.0, with exploratory biomarker work examining ERK/FAK dependence and co-mutations. Current treatment after surgery for newly diagnosed glioblastoma usually includes radiation with temozolomide, although temozolomide benefit is smaller in MGMT-unmethylated disease. This study instead asks whether ERK/FAK blockade can serve as a targeted partner for first-line radiation in that less chemotherapy-sensitive population.