Preliminary Safety, Efficacy, and Molecular Characterization of Emavusertib (CA-4948) in Relapsed/Refractory Acute Myeloid Leukemia Patients
Authors: Winer Eric S. , Sallman David , De la Fuente Burguera Adolfo , Verma Amit , Goetze Katharina , Abaza Yasmin , Dugan James P. , Cluzeau Thomas , Rodriguez Arboli Eduardo , Mims Alice , Groepper Stefanie , Zilbershatz Itay , Liesveld Jane L. , Fiedler Walter , Tarantolo Stefano R , Ades Lionel , Papadantonakis Nikolaos , Schliemann Christoph , Choudhary Gaurav S , Lane Maureen , Zhao Wanying , Jain Ashish , Gallagher Cole , Garcia-Manero Guillermo 
Published: December 2024

Background
Acute myeloid Leukemia (AML) is a heterogenous disease that exhibits a dynamic mutational landscape. Patients with relapsed/refractory (R/R) AML who have failed standard therapies, including venetoclax (VEN), hypomethylating agents (HMA), and/or FLT3 inhibitors (FLT3i) have limited therapeutic options. These patients often develop molecular mutations that lead to therapy resistance and poor overall survival. 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. In R/R AML patients with FLT3 mutations (FLT3m), these changes can also include mechanisms of adaptive resistance through compensatory activation of innate immune stress pathways via IRAK4. Emavusertib is a potent oral inhibitor of IRAK4, FLT3, 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 for emavusertib in patients with FLT3m and SFm who failed prior treatment with VEN, HMA, and/or FLT3i based regimens, either as a monotherapy or in combination. We also present safety data and molecular disease characterization.
Methods
The safety, clinical activity, and potential biomarkers of emavusertib in R/R AML and higher-risk myelodysplastic syndrome 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, 48 R/R AML patients with target mutations (FLT3, U2AF1 or SF3B1) and &lt; 3 lines of prior therapy were treated with emavusertib at a dose levels of 200-300 mg BID including 5 patients (2 FLT3m, 2 SFm and 1 dual mutation) dosed at 200 mg BID and 43 patients (14 FLT3m, 25 SFm and 4 dual mutation) dosed at 300 mg BID. In the 200 mg BID cohort, 1 patient with FLT3m and prior exposure to HMA, VEN and FLT3i had a response of morphologic leukemia-free state (MLFS) out of 5 response-evaluable patients. In 300 mg BID cohort, 9 patients were responders. The patients with FLT3m had 7 responses in 17 response-evaluable patients: 4 complete remission (CR), 1 CR with partial hematologic recovery (CRh) and 2 MLFS with on-treatment duration range of 85-324 days. Five patients with SFm had responses in 25 response-evaluable patients: 2 CR, 2 complete remission with incomplete and partial hematologic recovery (CRi/CRh) and 1 MLFS. Two patients with CRi and CR proceeded to stem cell transplantation. Among 9 responders, 8 responded after one cycle of treatment; 6 had prior exposure to VEN; 8 had prior exposure to HMA; 3 of 7 responding patients with FLT3m received prior FLT3i. The most frequent mutations in responding patients included genes involved in signaling pathways (NRAS), transcription factors (RUNX1, ASXL1), RNA splicing (U2AF1, SF3B1, SRSF2), tumor suppressors (WT1) and epigenetic modifiers (DMNT3A, BCOR). Emavusertib treatment significantly decreased the variant allele frequency of these mutations. FLT3-ITD levels were decreased or became undetectable in responders with FLT3m. As of 10 July 2024, 145 R/R AML (N=99) and hrMDS (N=46) patients received at least one dose of emavusertib at the dose levels of 200-500 mg BID. Treatment-related adverse events (TRAEs) Grade ≥ 3 were reported in 41 (28.3%) patients and most of them were reversible and manageable.
Conclusion
In R/R AML patients emavusertib demonstrated encouraging monotherapy anti-cancer activity in patients dosed at 300 mg BID with FLT3 and SFm having &lt; 3 lines of prior anti-cancer therapies, who had previously treated with VEN or HMA, and/or FLT3i. The mutation profiles of responders indicate that emavusertib may be able to target diverse underlying genetic mechanisms of resistance to VEN, HMA, or FLT3i regimens. These observations are suggestive of emavusertib's disease-modifying activity. Enrollment in this trial is ongoing at 300 mg BID in patients with &lt; 3 lines of prior anti-cancer therapies. Combination trials across the emavusertib program are ongoing with HMA, BCL2 and BTK-inhibitors.