Preliminary Safety, Efficacy and Molecular Characterization in Patients with Higher-Risk Myelodysplastic Syndrome Treated with Single Agent Emavusertib (CA-4948)
Authors: Garcia-Manero Guillermo , Sallman David , Tarantolo Stefano R , Verma Amit , Groepper Stefanie , Mims Alice , Abaza Yasmin , Dugan James P. , Gomez G De Soria Valle , Choudhary Gaurav S , Lane Maureen , Zhao Wanying , Jain Ashish , Gallagher Cole , Platzbecker Uwe 
Published: December 2024

Background
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies in older adults, marked by dysplastic hematopoiesis, cytopenias, and exhibit a dynamic mutational landscape as the disease progresses. In higher- risk MDS (hr-MDS), the primary treatment goal is to alter the natural progression of the disease, delaying the onset of acute myeloid leukemia and enhancing overall survival. However, current treatments are typically not curative, and many patients face relapse or resistance to first-line therapies. There is no definitive standard of care for many patients, highlighting the need for new, more effective, and tolerable management strategies for MDS. Splicing factor mutations (SFm) are frequently reported in AML and MDS and have been associated with disease progression and poor prognosis in relapsed/refractory (R/R) diseases. Splicing factors mutations (SFm) SF3B1 and U2AF1 drive interleukin-1 receptor-associated kinase 4 (IRAK4) mediated inflammatory pathway that is critical in oncogenesis, and survival of cancer cells. Emavusertib is a potent oral inhibitor of IRAK4, iFLT3, and CLK (1, 2, and 4), conferring preclinical efficacy advantages when compared with other IRAK4 or FLT3 inhibitors. Emavusertib inhibits the NF-kB and MAPK pathways, thus offering a potential mechanism to address known pathways of resistance to BCL2 and FLT3 inhibitors.
Aim
We present preliminary efficacy data of emavusertib hrMDS patients with SFm who failed prior treatment with either venetoclax (VEN) or hypomethylating agents (HMA) based regimens, either as monotherapy or in combination. This also includes safety data and molecular disease characterization.
Methods
The safety and clinical activity of emavusertib in R/R AML and hr-MDS are being investigated in the ongoing open-label, Phase 1/2 TakeAim Leukemia trial (NCT04278768). To characterize the mutational profiles of responders, targeted next generation sequencing of 68 genes was performed on genomic DNA from bone marrow or peripheral blood mononuclear cells at baseline and on treatment.
Results
As of 10 July 2024, 14 hrMDS patients with SFm (U2AF1, SF3B1) and &lt; 3 lines of prior therapy were treated with emavusertib at 300 mg BID. Preliminary data show 4 objective responses of marrow complete remission (mCR) in 13 response-evaluable patients with on-treatment duration of 28-260 days. Out of 14 treated patients, two patients proceeded to stem cell or bone marrow transplantation. To enhance potential efficacy of emavusertib to allow hematological recovery while maintaining malignant disease control, a cohort of R/R hrMDS patients is being recruited where the treatment period is reduced to 7 or 14 days (Arm A or B) in a 28-day cycle with emavusertib at 300 mg BID, to give the patients a dose holiday. As of July 10, 2024, 2 patients were enrolled in each arm. Two patients in this cohort archived mCR with on-treatment duration of 78 and 93 days, respectively and are still on treatment. Among responding patients in both cohorts: 2/6 had prior exposure to VEN; all had prior exposure to HMA. The most frequent mutations included genes involved in transcription factors (RUNX1, ASXL1), RNA splicing (U2AF1, SF3B1, SRSF2), and epigenetic modifiers (DMNT3A, TET2, BCOR). As of 10 July 2024, 145 R/R AML (N=99) and hrMDS (N=46) patients were treated with emavusertib at the dose levels of 200-500 mg BID. Treatment-related adverse events (TRAEs) Grade ≥ 3 were reported in 41 (28.3%) patients. The majority of Grade ≥ 3 TRAEs were reversible and manageable.
Conclusion
Emavusertib demonstrated encouraging anti-cancer activity in hrMDS patients dosed at 300 mg BID in continuous or 7- or 14-day dosing. The mutation profiles of responders indicate that emavusertib may be able to target diverse underlying genetic mechanisms of resistance to VEN or HMA regimens. These observations are suggestive of emavusertib's safety and disease-modifying activity. Enrollment in this monotherapy trial is ongoing at 300 mg BID in hrMDS patients with &lt; 3 lines of prior anti-cancer therapies. Combination trials across the emavusertib program are ongoing with HMA, BCL2 and BTK-inhibitors.