Intratumoral activity of ONC201 in adult recurrent glioblastoma patients.

e14034 Background: ONC201 is an antagonist of the G protein-coupled receptor DRD2 that crosses the blood-brain barrier and induces tumor cell apoptosis in preclinical models. The anti-tumor activity of ONC201 is pronounced in cells with low DRD5 expression and is associated with induction of the ATF4/CHOP/DR5-mediated integrated stress response pathway to trigger apoptosis. We previously reported the single agent activity of ONC201 in 17 adult patients with recurrent glioblastoma that demonstrated the safety, systemic pharmacodynamics, and a durable objective response when administered orally once every 3 weeks. Here, we evaluated the intratumoral drug concentrations and pharmacodynamic activity of ONC201 in adult recurrent glioblastoma patients who were treated on a weekly schedule. Methods: Six patients ≥18 years old with first recurrence of glioblastoma who were eligible for salvage surgical resection were enrolled. ONC201 was administered orally as 625 mg once a week. Salvage surgery was performed approximately 24 hours after the second dose of ONC201 and patients continued on ONC201 until radiographic and/or clinical progression. Tumor tissue was flash-frozen and formalin-fixed for assessments of intratumoral drug concentrations and pharmacodynamics, respectively. Results: Of the 6 enrolled patients, 5 had sufficient tissue for evaluation. Intratumoral drug concentrations exceeded therapeutic thresholds: median 1.5 µM (range 600 nM – 9.3 µM). Investigation of biomarkers related to downstream signaling induced by ONC201 revealed heterogeneous intratumoral induction of ATF4, CHOP, and DR5 expression along with tumor cell apoptosis (TUNEL). Stronger induction of the pharmacodynamic signaling biomarkers was associated with stronger induction of apoptosis and inversely associated with DRD5 expression, but not with drug concentration. No drug-related adverse events were reported in this cohort. Conclusions: ONC201 achieves intratumoral concentrations in recurrent glioblastoma patients that are well tolerated and result in pharmacodynamic signaling and tumor cell apoptosis.