Dr Sahin on the Investigation of Milademetan and ONC201 in Solid Tumors

Ilyas Sahin, MD, assistant professor, Division of Hematology & Oncology, University of Florida Health, discusses the investigation of milademetan (RAIN-32) in combination with imipridone ONC201 as a synergistic combination in solid tumors.

Various tumor types can harbor MDM2 amplifications, and researchers have developed inhibitors to block the MDM2-p53 interaction, such as milademetan, Sahin notes. Milademetan has been investigated in phase 1 and 2 trials, and it is currently under investigation in the phase 3 MANTRA trial (NCT04979442) in patients with dedifferentiated liposarcoma.

ONC201 is an orally active, small molecule DRD2 antagonist used in the treatment of patients with various tumor types, Sahin continues. The rationale for combining these 2 drugs is because MDM2-p53 inhibitors such as milademetan can increase levels of MDM2, which could lead to immune-mediated adverse effects independent of the p53 pathway, Sahin says. Additionally, MDM2 amplification is potentially predictive for hyper-progressive disease, Sahin explains. Adding ONC201 a MDM2-p53 inhibitor such as milademetan could inhibit MDM2 levels, Sahin adds.

Findings from a preclinical study of the combination of milademetan and ONC201 were presented at the 2023 AACR Annual Meeting, which identified an additional effect of ONC201 in significantly reducing detectable MDM2 levels in cell lines, suggesting synergy of the combination of ONC201 with milademetan. Additional research is underway, exploring this combination in mice, and the hope is to eventually progress to a first-in-human trial, Sahin says. If data continue to be positive, this strategy could represent a novel and translatable therapeutic approach for the treatment of patients with MDM2-overexpressing tumors, Sahin says. Investigators are also interested in testing this combination used in conjunction with immune checkpoint blockade since MDM2 amplification may have a role for immunotherapy resistance, Sahin concludes.