Analysis of genetic mutation profile and CNS pharmacokinetics in relapsed/refractory primary CNS lymphoma patients responding to novel emavusertib (IRAK4i) and BTKi combination.

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2085 Background: Primary Central Nervous System Lymphoma (PCNSL) is a rare and aggressive non-Hodgkin lymphoma with no approved treatments for relapsed/refractory (R/R) patients, representing a critical unmet need. MyD88 mutations in ~70% of PCNSL patients drive Interleukin-1 receptor associated kinase 4 (IRAK4) activation, promoting NF-κB signaling, inflammation, and tumor progression. Emavusertib, a potent oral IRAK4 inhibitor, crosses the blood-brain barrier and shows preclinical synergy with Bruton tyrosine kinase inhibitors (BTKi), re-sensitizing BTKi-resistant cell lines. This study evaluates the molecular and pharmacokinetic (PK) data associated with responses to emavusertib + ibrutinib combination therapy in R/R PCNSL patients. Methods: The safety, clinical activity, and potential biomarkers of emavusertib in R/R PCNSL are being investigated in the ongoing open-label, Phase 1/2 TakeAim Lymphoma trial (NCT03328078). Pre-dose and 1.5-hour post-dose plasma samples were collected on Cycle 3 Day 1, Cycle 5 Day 1 and Cycle 7 Day 1. Cerebrospinal fluid (CSF) samples were obtained via a lumbar puncture within 1.5 hrs of collection of the post-dose plasma PK sample on Cycle 3 Day 1. Mutation analysis was based on patients’ molecular pathology reports provided by trial sites. Sequencing of archival tissues, CSF and plasma are in progress. Results: As of 06 December 2024, CSF concentration data were available for 7 PCNSL patients. The mean emavusertib concentration in CSF was 81.3 ng/ml (54.7-104.0) in patients receiving 100 mg emavusertib BID (n = 4). In patients receiving 200 mg emavusertib BID (n = 3), the mean emavusertib concentration in CSF was higher at 175.7 ng/ml (114.8-209.4), which is 2.2X the mean value in patients who received 100 mg emavusertib BID (p-value = 0.02). All 7 patients received 560 mg ibrutinib QD, and the ibrutinib concentrations in the CSF were consistent with findings from previously published clinical studies. MyD88 mutation status was available for 7 patients of which all had prior exposure to BTKi regimens. Among these, 6 patients had MyD88 mutation of which 4 patients had responded (3 complete responses and 1 partial response) to emavusertib + ibrutinib combination with duration of response (DOR) up to 18.9 months with data collection ongoing. Conclusions: Preliminary CNS pharmacokinetic data demonstrates that emavusertib concentration in CSF increases with increasing emavusertib dose. Patients with MyD88 mutations showed expected promising preliminary efficacy to emavusertib + ibrutinib combination and may overcome BTKi resistance. Enrollment in this trial is ongoing. Clinical trial information: NCT03328078 .