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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.

Background: Emavusertib (CA-4948) is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), which is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in B cell proliferation. Additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4) is also present in emavusertib. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation ofnuclear factor-kappa B (NF-κB), causing inflammation and tumor growth. Emavusertib has been reported to be well tolerated and active as monotherapy in heavily pretreated patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) (Nowakowski 2020). Preclinical studies demonstrated that tumor resistance and survival via IRAK4 activation could be delayed or reversed. Emavusertib crossed the blood-brain barrier in a murine PDX model of PCNS lymphoma, blocked the activated IRAK4 pathway, and induced tumor response and prolonged survival (von Roemeling 2022). In combination with Bruton tyrosine kinase (BTK) inhibitors, emavusertib showed in vitro synergy and re-sensitization of resistant cell lines, overcoming BTK resistance (Guidetti 2023a and 2023b). In vivo synergy in B-cell NHL was also demonstrated. Adaptive chemotherapy treatment resistance through IRAK4 upregulation and activation was also described in other disease models (Melgar 2019, Li 2019). This abstract presents preliminary efficacy and safety data of emavusertib + ibrutinib in R/R NHL patients. Aim:Assessment of safety and clinical activity of emavusertib in combination with ibrutinib. Methods: This is an ongoing open-label trial (NCT03328078) of emavusertib as monotherapy and in combination with ibrutinib. Part A1 - completed; dose escalation of emavusertib as monotherapy; the recommended phase 2 dose (RP2D) is 300 mg BID with continuous oral dosing (Nowakowski 2020). Part A2 - completed; dose escalation of emavusertib in combination with ibrutinib at 420 and 560 mg QD (Joffe 2022). Part B - ongoing; an expansion cohort of PCNSL patients with resistance to prior BTK inhibitors for additional safety and efficacy related to exposure: emavusertib at 100 or 200 mg BID + ibrutinib at 560 mg QD in 28-Day cycles. Results:As of 19 July 2023, 18 heavily pretreated NHL (including five PCNSL) patients received emavusertib at 100, 200, or 300 mg BID in combination with full ibrutinib doses per label. Median age was 63.5 years (range 50-92). Median number of prior lines of anti-cancer therapies was 3 (range 1-10). Eleven of 18 patients failed prior BTK inhibitors. Median treatment duration was 95.5 days (21-587 days), suggesting acceptable safety and tolerability. No DLTs were observed at the 200 mg BID dose level, and two reversible DLTs (stomatitis and syncope) were observed at the 300 mg BID dose level. The preliminary efficacy data of 16 evaluable patients in combination with ibrutinib showed 5 CRs (2 MCL, 3 PCNSL) and 1 PR (1 CLL). All 3 PCNSL patients with CR were previously treated with BTK inhibitors. Conclusion: The combination ofemavusertib plus ibrutinib (ema+ibr) is well tolerated with an acceptable long-term safety profile and promising efficacy, showing several objective responses in heavily pretreated and/or BTK inhibitor resistant patients. Emavusertib may have the potential to overcome BTK inhibitor resistance and the combination of ema+ibr has the potential to show increased anti-cancer activity compared to ibrutinib monotherapy.

Abstract Aims To investigate valve sizing and the haemodynamic relevance of the predicted left ventricular outflow tract (LVOT) in patients with mitral annular calcification (MAC) undergoing transatrial transcatheter valve implantation (THV). Methods and results In total, 21 patients undergoing transatrial THV, multiplanar reconstruction (MPR), maximum intensity projection (MIP), and cubic spline interpolation (CSI) were compared for MA sizing during diastole. In addition, predicted neo-LVOT areas were measured in 18 patients and correlated with the post-procedural haemodynamic dimensions. The procedure was successful in all patients (100%). Concomitant aortic valve replacement was performed in eight patients (43%) (AVR group). Sizing using MPR and MIP yielded comparable results in terms of area, perimeter, and diameter, whereas the dimensions obtained with CSI were systematically smaller. The simulated mean systolic neo-LVOT area was 133.4 ± 64.2 mm2 with an anticipated relative LVOT area reduction (neo-LVOT area/LVOT area × 100) of 59.3 ± 14.7%. The systolic relative LVOT area reduction, but not the absolute neo-LVOT area, was found to predict the peak (r = 0.69; P = 0.002) and mean (r = 0.65; P = 0.004) post-operative aortic gradient in the overall population as well as separately in the AVR (peak: r = 0.91; P = 0.002/mean: r = 0.85; P = 0.002) and no-AVR (peak: r = 0.89; P = 0.003/mean: r = 0.72; P = 0.008) groups. Conclusion In patients with severe MAC undergoing transatrial transcatheter valve implantation, MPR, and MIP yielded comparable annular dimensions, while values obtained with CSI tended to be systematically smaller. Mitral annular area and the average annular diameter appear to be reliable parameters for valve selection. Simulated relative LVOT reduction was found to predict the post-procedural aortic gradients.