Schmitt, Anna

Abstract PCNSL is a rare and aggressive NHL with no approved treatments for R/R patients, representing a critical unmet need. MyD88 mutations in ~70% of PCNSL patients drive 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 BTKis, and has the ability to re-sensitize BTKi-resistant cell lines. This study evaluates the molecular and PK data associated with responses to emavusertib + ibrutinib combination therapy in R/R PCNSL patients. The safety, clinical activity, and potential biomarkers of emavusertib in R/R PCNSL are being investigated in the ongoing TakeAim Lymphoma trial (NCT03328078). Pre-dose and 1.5-hour post-dose plasma samples were collected on Day 1 of Cycles 3, 5, and 7. 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. As of 06 December 2024, CSF concentration was available for 7 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 2.2 × the mean value in patients who received 100 mg emavusertib BID (p-value = 0.02). MyD88 mutation status was available for 7 patients of which all had prior BTKi exposure. Among these patients, 6 had MyD88 mutations of which 4 had responded (3 CRs and 1 PR) to the combination with DOR up to 18.9 mos with data collection ongoing. Preliminary CNS PK data demonstrate 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 is ongoing.

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 .