CTNI-38. PHASE 1 DOSE ESCALATION OF EO1001, AN ORAL BRAIN-PENETRATING PAN-ERBB INHIBITOR, IN ADVANCED CANCER: PRELIMINARY RESULTS FROM AN ONGOING PHASE 1–2A CLINICAL TRIAL

Abstract BACKGROUND Central nervous system (CNS) metastases are a major cause of cancer-related morbidity and mortality, particularly as systemic therapies extend survival. Mutations in the ErbB/HER family of kinases are commonly associated with CNS progression in multiple malignancies. EO1001 is a novel, oral, blood brain-penetrating, irreversible pan-ErbB inhibitor targeting EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4). In preclinical models, EO1001 rapidly enters the CNS, achieving concentrations exceeding those in plasma, effectively inhibiting downstream ErbB signaling and improving outcomes compared to controls in orthotopic, ErbB-positive tumor models, including N87 (HER2+), H1975 (EGFR/T790M), GBM12 (EGFR+), and GBM39 (EGFRvIII+). Here, we report initial results from the Phase 1 dose escalation portion of an ongoing Phase 1–2a trial in patients with advanced solid tumors, including those with CNS involvement. METHODS EO1001 is being evaluated in a multicentre, open-label Phase 1–2a study. The dose-escalation phase uses an accelerated dose titration design, transitioning to a standard 3 + 3 scheme following ≥ grade 2 drug-related toxicity. Safety is assessed using CTCAE v5.0. Pharmacokinetic profiling and preliminary anti-tumor activity, including CNS response, are also evaluated. RESULTS Nineteen patients were treated across seven dose cohorts (2.5–90 mg/day). EO1001 was well tolerated at lower doses. Dose-limiting toxicities, consistent with other agents in the class, were observed at 70 and 90 mg/day of continuous once daily dosing. Signs of anti-tumor activity, including in patients with known CNS involvement and resistance to prior anti-Her2 therapy, were noted at doses ≥20 mg/day. Pharmacokinetic data revealed linear and dose-proportional increases in systemic exposure, consistent with preclinical rodent models. CONCLUSIONS EO1001 demonstrates early evidence of clinical activity at dose and exposure levels predicted to be therapeutically relevant based on preclinical data. Enrollment is ongoing in a Phase 2 expansion cohort to further assess safety and CNS-targeted efficacy at or below the MTD.