IRAK-4 Inhibitor CA-4948 May Enhance Immunotherapeutic Outcomes in Melanoma With Brain Metastases

Source: OncLive, May 2023

Promising preclinical findings have demonstrated that IRAK-4 is a viable target to increase the efficacy of immunotherapy in patients with melanoma who have brain metastases. The development of the oral, IRAK-4 inhibitor, CA-4948, showed enhanced antitumor activity and efforts are underway to evaluate the agent in combination with pembrolizumab (Keytruda) in a first in-human clinical trial (NCT05669352), according to Bently Doonan, MD.

“We’re starting to gather more information about the tumor microenvironment,” Doonan explained. “Understanding how we can manipulate or effect the tumor microenvironment to make immunotherapies work better is going to be vital to expanding their scope, efficacy, and impact [of these agents]. We [hypothesize] that the IRAK-4 inflammatory mitosomal pathway and the ability to inhibit it with drugs [such as] CA-4948 has the potential to open those doors.”

According to murine data published in Clinical Cancer Research in February 2023, high-dose CA-4948 monotherapy (100 mg/kg) vs CA-4948 vehicle in specimens harboring B16F10 central nervous system (CNS) melanoma tumors improved the mean overall survival by 35%. The median survival was 17.0 days for mice receiving the therapy compared with 12.6 days for mice receiving vehicle. Investigators also noted that there was markedly reduced tumor burden observed in brain tissue isolated on day 7 of treatment.2