Dr Doonan on the Evaluation of IRAK-4 Inhibition With Emavusertib in Metastatic Brain Melanoma

Bently P. Doonan, MD, assistant professor, Division of Hematology & Oncology, University of Florida (UF), UF Health, discusses the evaluation of targeted inhibition of IRAK-4 with emavusertib (CA-4948) in the treatment of metastatic brain melanoma.

A preclinical study presented at the 2023 AACR Annual Meeting used immunohistochemistry (IHC) to assess samples from patients with metastatic brain melanoma to define the distribution of myddosome signaling. The models were treated with emavusertib alone and in combination with an immune checkpoint inhibitor. Flow cytometry and IHC were also used to characterize the immune microenvironment.

Although the vast majority of drugs are unable to effectively penetrate the blood-brain barrier, especially in a therapeutic concentration, emavusertib was found to get into the brain, Doonan emphasized. Investigators wanted to investigate this agent in a solid tumor with an integral tumor microenvironment, leading to the focus on metastatic brain melanoma, Doonan says.

Previous literature showed that melanoma cells upregulate IRAK-4, Doonan notes, adding that this is done in response to inflammation. Although immunotherapy has an established role in the treatment of melanoma, approximately half of patients will not benefit from immunotherapy, partially due to inflammation associated with melanoma since inflammation could lead to the environment to become suppressive, Doonan explains.

Emavusertib blocks IRAK-4, affecting how cells utilize inflammation slowing their growth rate, Doonan notes. More importantly, emavusertib appeared to regulate the tumor microenvironment, which could improve the efficacy of standard immunotherapy with a checkpoint inhibitor, Doonan says. In aggressive, resistant mouse models for metastatic melanoma, including cell lines that do not traditionally respond to immunotherapy, there was improvement in the survival of these mice by adding emavusertib to a checkpoint inhibitor, Doonan concludes.