Ctni-59. Analysis of Genetic Mutation Profile and Cns Pharmacokinetics in Relapsed/refractory Primary Cns Lymphoma Patients Responding to Novel Emavusertib (irak4i) and Btki Combination
Year: 2025
Type: conference-abstract
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.
Source: Neuro-Oncology
Authors: Christian Grommes, MD, Anna Dabrowska-Iwanicka, MD, Han W Tun, MD, Christopher R D’Angelo, MD, Adolfo De La Fuente, MD, Itai Levi, MD, Lakshmi Nayak, David Lavie, Alessia Castellino, MD, Michael Taszner, MD, Praveen Ramakrishnan Geethakumari, MD, MS, MBA, Laurence Schenone, MD, Andrés J M Ferreri, MD, Teresa Calimeri, MD, Luca Nassi, MD, Caroline Houillier, MD, Anna Schmitt, MD, Maureen E Lane, PhD, Wanying Zhao, PhD, Grzegorz Nowakowski, MD
Institutions: Memorial Sloan Kettering Cancer Center, The Maria Sklodowska-Curie National Research Institute of Oncology, Mayo Clinic in Florida, Mayo Clinic Comprehensive Cancer Center (Florida), University of Nebraska Medical Center, MD Anderson Cancer Center Madrid, Soroka Medical Center, Dana-Farber Cancer Institute, Hadassah Medical Center, Azienda Sanitaria Ospedaliera S.Croce e Carle Cuneo, Gdańsk Medical University, Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Hôpital de la Timone, IRCCS Ospedale San Raffaele, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Sorbonne Université, Pitié-Salpêtrière Hospital, Institut du Cerveau, Institut Bergonié, Curis (United States), Mayo Clinic
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416140187
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