Preliminary Safety and Efficacy of Emavusertib (CA-4948) in Combination with Ibrutinib in Relapsed/Refractory Primary Central Nervous System Lymphoma Patients with Prior Exposure to BTK Inhibitor

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).

Nowakowski:Debiopharm: Consultancy; Curis: Consultancy, Research Funding; Karyopharm Therapeutics: Consultancy; MorphoSys AG: Consultancy, Research Funding; Constellation Pharmaceuticals: Consultancy; Blueprint Medicines Corporation: Consultancy; Daiichi Sankyo: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; F. Hoffmann-La Roche Limited: Consultancy; Segen: Consultancy; Selvita Inc: Consultancy; Incyte Corporation: Consultancy; Celgene Corporation: Consultancy, Research Funding; AbbVie Inc.: Consultancy; Bantam Pharmaceutical, LLC: Consultancy; TG Therapeutics Inc: Consultancy; ADC Therapeutics: Consultancy; Ryvu Therapeutics: Consultancy; Fate Therapeutics: Consultancy; MEI Pharma: Consultancy; Kymera Therapeutics: Consultancy; Zai Laboratory: Consultancy; Genentech: Consultancy. Tun:Gossamerbio: Research Funding; Curis: Consultancy. Ramchandren:Pfizer BMS (institutional): Research Funding. Choudhary:Curis: Current Employment. Zhao:Curis: Current Employment. Ferrari:Curis: Current Employment. Fowle:Curis: Current Employment. Lane:Curis: Current Employment. Wang:Curis: Current Employment. Taszner:Takeda: Consultancy, Speakers Bureau; Roche: Consultancy; Beigene: Consultancy, Speakers Bureau.

Ibrutinib, a BTK inhibitor is commonly used in CNS lymphoma. 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.