Dąbrowska‐Iwanicka, Anna

Abstract There are no approved treatments for relapsed/refractory (R/R) PCNSL. We show promising efficacy in the salvage setting using emavusertib in combination with ibrutinib, which targets the BCR and TLR pathways. These 2 major pathways are associated with activation of NF-κB. Updated safety and efficacy data of this combination in R/R PCNSL from the ongoing Phase 1/2 TakeAim Lymphoma trial (NCT03328078) will be presented. As of 01 May 2025, 33 patients with R/R PCNSL were treated with emavusertib in combination with ibrutinib. Eligible patients receive emavusertib in combination with ibrutinib until tumor progression or unacceptable toxicity. Median age was 63 years (range 43-81); 16 patients were male. Median prior anti-cancer therapy was 2 (range 1-5); 26 (78.8%) patients had prior BTKi exposure. Median duration of emavusertib/ibrutinib treatment was 51 days (range 5-798). Grade ≥ 3 treatment-related adverse events (TRAEs) were reported in 11 (33.3%) patients; neutropenia in 5 (15.2%) patients, amylase increased, lipase increased, and leukopenia in 2 (6.1%) patients each. The majority of Grade ≥ 3 TRAEs were reversible and manageable. Among the 19 BTKi-experienced patients treated for ≥ 28 days, there were 5 CRs and 2 PRs, with an ORR of 36.8%. Three patients with CR were on treatment for 10+ mos, with 1 CR patient ongoing with DOT of 26.2+ mos. Among the 5 BTKi-naïve patients treated for ≥ 28 days, 1 achieved CR and 3 had PR, with ORR of 80%; the CR patient is ongoing with DOT of 18.1+ mos. The ORR in the combined population was 45.8% (6 CRs; 5 PRs). The combination of emavusertib and ibrutinib demonstrates promising clinical activity and an acceptable safety profile in patients with R/R PCNSL. This regimen appears capable of overcoming resistance to prior BTKi therapy. Patient enrollment in this trial continues.

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 .

Background Primary Central Nervous System Lymphoma Patients (PCNSL) is a rare and aggressive form of NHL in the central nervous system or vitreoretinal space. Despite high initial response rates of high dose methotrexate-based regimens, most patients will relapse in less than two years with poor prognosis. There are no approved treatments for Relapsed/Refractory (R/R) PCNSL, representing a clear unmet medical need. IRAK4 kinase activity is required for TLR and IL-1R signaling in a variety of myeloid and lymphoid cell types, including PCNSL. Recruitment of IRAK4 to these receptors and subsequent activation is facilitated by the MyD88 adaptor protein, which is mutated in ~70% of PCNSL. This leads to constitutive activation of the NF-κB signaling pathway, increased inflammation, and tumor growth. Emavusertib is a novel and potent oral inhibitor of IRAK4, which has demonstrated the ability to cross the blood-brain barrier in PCNSL xenografts. In preclinical studies, the combination of emavusertib with Bruton tyrosine kinase inhibitors (BTKi) showed in vitro synergy of inhibition and re-sensitization of BTKi-resistant cell lines. Emavusertib + ibrutinib has demonstrated an acceptable safety profile across a broad population of R/R NHL patients, including PCNSL. Aim We present updated safety and efficacy of emavusertib in combination with ibrutinib in patients with R/R PCNSL most recently treated with BTKi regimen. 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). The eligible patients with R/R PCNSL received emavusertib (100-300 mg BID) in combination with ibrutinib (560 mg QD) continuously until tumor progression or unacceptable toxicity. Disease staging at screening and anti-cancer therapeutic responses were evaluated according to the IPCG Response Criteria Guideline for PCNSL. Results As of 10 July 2024, 13 R/R PCNSL patients, with prior BTK exposure, received emavusertib at 100 - 300 mg BID in combination with ibrutinib at 560mg QD. The median age was 60 years (range 44 - 79). The median number of prior lines of anti-cancer therapies was 2 (range 2 - 5). Median emavusertib/ibrutinib treatment duration was 51 days (range 17 - 503). The preliminary efficacy data in 12 evaluable patients whose most recent treatment regimen included a BTKi and were treated with the combination of emavusertib and ibrutinib showed 3 complete remission (CR), 1 unconfirmed complete Response (CRu) and 2 partial responses (PR) and an overall response rate of 50%. Treatment is on-going for 5 patients with one patient pending the first assessment. All responders demonstrated more than 80% reduction in target lesion size compared to baseline. Two of the responders with a CR demonstrated durable response, with 1 patient having a duration of response (DOR) of approximately 9 months, and the second patient having a DOR of 12 months with response ongoing. Grade ≥3 Treatment-emergent adverse events (TEAEs) were reported in 7 (53.8%) patients, while Grade ≥3 treatment-related adverse events (TRAEs) were reported in 4 (30.8%) patients. No fatal TRAE were reported and the majority of Grade ≥ 3 TEAEs and all Grade ≥ 3 TRAEs were reversible and manageable. Conclusion Emavusertib in combination with ibrutinib shows promising efficacy and was well tolerated with an acceptable safety profile in R/R PCNSL patients with prior BTKi exposure. The combination of emavusertib + ibrutinib may overcome BTKi resistance and has the potential to show improved anti-cancer activity. Enrollment in this trial is ongoing (NCT03328078).

2087 Background: PCNSL is a rare and aggressive form of NHL in the central nervous system or vitreoretinal space. Despite high initial rates of responses to HD-MTX-based induction chemotherapies, most patients relapse in two years. R/R PCNSL is associated with poor prognosis, representing a clear unmet medical need, as there are no currently approved treatments for this disease. IRAK4 kinase activity is required for TLR and IL-1R signaling in a variety of myeloid and lymphoid cell types, including PCNSL. Recruitment of IRAK4 to these receptors and subsequent activation is facilitated by the MyD88 adaptor protein, which is mutated in ~70% of PCNSL. This leads to constitutive activation of the NF-κB signaling pathway, increased inflammation, and tumor growth. Emavusertib is a novel and potent oral inhibitor of IRAK4 and FLT3, which has demonstrated the ability to cross the blood-brain barrier in PCNSL xenografts. In preclinical studies, the combination of emavusertib with ibrutinib overcomes resistance to BTK inhibitors. This combination has an acceptable safety profile across a broad population of R/R NHL patients, including PCNSL. Here we present updated safety and efficacy data for emavusertib in combination with ibrutinib in patients with R/R PCNSL. 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). The eligible patients with R/R PCNSL received emavusertib (100-300 mg BID) in combination with ibrutinib (560 mg QD) in a 21-day cycle until tumor progression or unacceptable toxicity. Results: Here, we present updated data from R/R PCNSL patients with prior ibrutinib exposure who were treated with emavusertib in combination with ibrutinib. The median number of prior lines of anti-cancer therapies was 3 (range: 2-5), all patients were R/R to both frontline therapy and subsequent ibrutinib regimens. Prior responses to ibrutinib based regimens included only 1 CR. Here, we report a higher CR rate when these patients are subsequently treated with emavusertib in combination with ibrutinib.Results revealed no dose-limiting toxicities. Conclusions: Emavusertib in combination with ibrutinib was well tolerated with an acceptable safety profile and promising efficacy in R/R PCNSL patients with previous exposure to ibrutinib (BTKi). Enrollment in this trial is ongoing (NCT03328078). Clinical trial information: NCT03328078 .

Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of NHL isolated to the central nervous system or vitreoretinal space. Despite high initial rates of responses to available therapies, most PCNLS relapse in two years, presenting a very poor prognosis. Combination with novel therapies may overcome resistance (Guidetti 2023a). Upregulation of the B-cell receptor (BCR/NF-κB) and toll-like receptor (TLR)/NF-κB) signaling axis have been identified as key pathways in the pathogenesis of PCNSL. MYD88 L265P, a widely expressed somatic mutation in more than 70% of PCNSL patients, activates NF-κB signaling through stimulation of BTK and IRAK4. Emavusertib (CA-4948) is a novel, potent oral inhibitor of interleukin 1 receptor-associated kinase 4 (IRAK4), with additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4). Targeted inhibition of IRAK4 with emavusertib in PCNSL xenografts indicated sufficient blood brain barrier penetration of emavusertib, target inhibition, and antitumor activity (von Roemeling 2022). Further preclinical studies have demonstrated that emavusertib synergizes with ibrutinib and can re-sensitize and overcome resistance to BTK inhibitors (Guidetti 2023a and 2023b). Initial clinical data have reported responses in BTK-resistant PCNSL and good tolerance of the combination (Iqbal 2022; Grommes 2023). Study Design: This is an ongoing multi-center, open-label trial (NCT03328078) in adult patients with hematologic malignancies to evaluate the safety, PK, and anti-cancer activity of oral administration of emavusertib alone or in combination with ibrutinib. Part Bis an open trial expansion cohort with BTKi relapsed or refractory PCNSL. About 20 evaluable PCNSL patients will be enrolled globally. Patients will receive oral CA-4948 at 100 or 200 mg BID in combination with ibrutinib at 560 mg QD in 28-day cycles until disease progression or intolerable toxicity. The primary endpoint is expanded safety/tolerability; secondary endpoints include ORR, DOR, PFS, OS, and pharmacokinetics. Key inclusion criteria for this expansion cohort: pathologically confirmed diagnosis of PCNSL with evidence of disease progression, measurable disease, relapsed or refractory with no more than 3 lines of prior anti-PCNSL therapy (including BTKi), and absence of residual Grade ≥2 toxicity from prior therapy. Key exclusion criteria: intraocular PCNSL without brain lesion or CSF involvement or significant co-morbidity. Key clinical assessments include brain imaging, CSF- and ocular examinations.

Abstract Diffuse large B-cell lymphoma (DLBCL), not otherwise specified, is the most common subtype of large B-cell lymphoma, with differences in prognosis reflecting heterogeneity in the pathological, molecular, and clinical features. Current treatment standard is based on multiagent chemotherapy, including anthracycline and monoclonal anti-CD20 antibody, which leads to cure in 60% of patients. Recent years have brought new insights into lymphoma biology and have helped refine the risk groups. The results of these studies inspired the design of new clinical trials with targeted therapies and response-adapted strategies and allowed to identify groups of patients potentially benefiting from new agents. This review summarizes recent progress in identifying high-risk patients with DLBCL using clinical and biological prognostic factors assessed at diagnosis and during treatment in the front-line setting, as well as new treatment strategies with the application of targeted agents and immunotherapy, including response-adapted strategies.