Dr Nayak on the Ongoing Investigation of Emavusertib Plus Ibrutinib in R/R PCNSL

“We are investigating the role [of emavusertib plus ibrutinib] in terms of efficacy. The population that is being studied [includes] patients who have progressed after BTK inhibition. We’re looking to target that mechanism of resistance to [BTK inhibition] in that regard, rather than target patients who never responded to BTK inhibition, which is a fraction of the patients.”

Lakshmi Nayak, MD, director, Center for Central Nervous System (CNS) Lymphoma, senior physician, Dana-Farber Cancer Institute; and associate professor, neurology, Harvard Medical School, discusses the mechanism of action of emavusertib (CA-4948) and how this mechanism provides the rationale for the drug’s ongoing investigation in combination with ibrutinib (Imbruvica) in patients with relapsed/refractory primary and secondary CNS lymphoma (PCNSL) in the part B expansion cohort of the phase 1/2 TakeAim Lymphoma trial (NCT03328078).

Emavusertib, an IRAK4 inhibitor, is being explored for its potential in treating patients with PCNSL, Nayak begins. One key advantage of this compound is its ability to cross the blood-brain barrier, a significant challenge in treating patients with brain tumors, she says. In preclinical studies, the agent demonstrated blood-brain barrier penetration, as well as activity against BTK-resistant cell lines, she notes. This is particularly relevant as resistance to BTK inhibitors, such as ibrutinib, poses a major hurdle in lymphoma management, particularly for patients with PCNSL, Nayak explains. The ability of this IRAK4 inhibitor to maintain activity in BTK-resistant models positions it as a potential next step in treatment after resistance to BTK inhibition develops, she reports. For patients who have initially responded to BTK inhibitors but later progressed, combinations containing this IRAK4 inhibitor could offer a strategy to target the resistance and restore efficacy, according to Nayak. In addition, there is potential for this agent to be explored in earlier lines of therapy, either alone or in combination with chemotherapy, to improve patient outcomes from the outset, she emphasizes.

Emavusertib has been studied in various oncologic indications, including both myeloid and lymphoid malignancies, Nayak notes. A safety study involving patients with PCNSL showed that the combination of the IRAK4 inhibitor with ibrutinib was well tolerated, she adds. Moving forward, part B of the TakeAim Lymphoma trial is investigating the efficacy of this regimen in patients with PCNSL who have progressed after previously achieving a response with a BTK inhibitor, with the hope of addressing resistance and improving outcomes in this challenging-to-treat patient population, Nayak concludes.