Supplements and Featured Publications
Targeted Approaches Under Assessment in AML
Volume 1
Issue 1

Emavusertib Monotherapy Shows Antitumor Activity, Safety in Select R/R AML and High-Risk MDS

Key Takeaways

  • Emavusertib demonstrated over 90% reduction in bone marrow blasts in responsive patients.
  • Complete responses were observed in patients with FLT3-mutant AML and spliceosome mutations.
Eric S. Winer, MD

Eric S. Winer, MD

Emavusertib (CA-4948) demonstrated manageable safety and anti-leukemic activity in patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome who expressed FLT3, U2AF1, or SF3B1 mutations, including those who previously progressed on FLT3 inhibitor–based regimens, according to preliminary data from the phase 1/2 TakeAim Leukemia study (NCT04278768) presented during the 2024 ASCO Annual Meeting.1

Findings showed that patients who experienced a response with emavusertib demonstrated more than a 90% reduction in bone marrow blasts compared with baseline. Among evaluable patients with FLT3-mutant AML (n = 11), complete responses (CR) were observed in 3 patients, complete response with partial hematologic recovery (CRh) was achieved by 1 patient, and 2 patients achieved a morphological leukemia-free state (MLFS). In evaluable patients with AML harboring spliceosome mutations (n = 15), 1 CR, 1 MLFS, and 2 CR/CRh responses were reported. The median time to response (TTR) in the FLT3-mutant group was 29 days; this was 28.5 days in the spliceosome-mutated group.

Further assessment of clinical activity in responders with FLT3-mutant AML revealed that 2 of the 3 patients who achieved a CR were not previously exposed to a FLT3 inhibitor and had intermediate-risk disease according to European LeukemiaNet (ELN) risk classifications. One of these patients received 1 prior therapy and had U2AF1, BCOR and WT1 mutations at baseline; the other patient received 2 prior therapies and had DMNT3A and SRSF2 mutations. The third patient with a CR had prior exposure to a FLT3 inhibitor, had adverse-risk disease, previously received 2 lines of therapy, and had NRAS and WT1 mutations.

Of the 2 patients who achieved MLFS, both had received 2 prior lines of therapy and had adverse-risk disease. One patient had not received a prior FLT3 inhibitor; this patient expressed SF3B1, GATA2, PHF6, RUNX1, and CBLC mutations at baseline. The other patient had prior exposure to a FLT3 inhibitor but did not have co-mutation data available. The patient who achieved a CRh as their best response had intermediate-risk disease, had 1 prior line of therapy, and was previously exposed to a FLT3 inhibitor; no co-mutation data were available for this patient.

“The mutation profiles of responders indicate that emavusertib may be able to target diverse underlying genetic mechanisms of resistance to prior FLT3 inhibitor regimens,” lead study author Eric S. Winer, MD, physician and clinical director of Adult Leukemia at Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues, wrote in a poster presentation of the data. “This is suggestive of the disease-modifying activity of emavusertib.”

AML is considered a highly heterogeneous disease, with a dynamic mutational landscape throughout the disease course. A key acquired late-event mutation in AML is internal tandem duplication (ITD) of the FLT3 mutation, which is linked with poor prognosis. Additionally, mutations in the splicing factors (SF) SF3B1 and U2AF1 have been identified as key drivers of IRAK4 overexpression, which plays a role in inflammatory response, oncogenesis, and cancer cell survival.

Preclinical data have demonstrated superior efficacy with the potent oral IRAK4, FLT3, and CLK inhibitor emavusertib vs other IRAK4 or FLT3 inhibitors. Moreover, dual inhibition of IRAK4 and FLT3 with emavusertib can target mechanisms of adaptive resistance in patients with relapsed/refractory AML; this agent may also address resistance to BCL2 and FLT3 through inhibition of the NF-kB and MAPK pathways.

The multicenter, open-label TakeAim Leukemia study evaluated the safety, clinical activity, and potential biomarkers of efficacy for emavusertib in patients with relapsed/refractory AML expressing FLT3 mutations, as well as those with relapsed/refractory AML or higher-risk MDS expressing spliceosome mutations. Higher-risk MDS was defined as an IPSS-R score greater than 3.5. Patients’ molecular profiles were documented according to local testing results. Bone marrow and peripheral blood samples were collected at baseline and during treatment.1,2

Eligible patients were required to have a life expectancy of at least 3 months, an ECOG performance status of 1 or less, adequate organ function, and the ability to undergo serial bone marrow sampling and peripheral blood sampling.2 Exclusion criteria included active central nervous system disease, active advanced malignant solid tumors, and treatment with any systemic anticancer therapy within 3 weeks prior to starting treatment with emavusertib.

In the dose-escalation phase, patients received emavusertib at 200 mg, 300 mg, 400 mg or 500 mg twice a day.1 The recommended phase 2 dose (RP2D) was identified as 300 mg twice daily. A total of 123 patients were treated with emavusertib and had available safety data, 84 and 39 of whom had AML or MDS, respectively. Among those with AML, 12 expressed a FLT3 mutation and 20 harbored a U2AF1 or SF3B1 mutation. Notably, 2 patients with AML expressed both a spliceosome and FLT3 mutation.

The primary objective of the phase 1 portion was to determine the maximum tolerated dose and RP2D of emavusertib.2 In the phase 2 portion, the primary objective was to assess the anticancer activity of emavusertib monotherapy at the RP2D. Key secondary end points included pharmacokinetics, response rates, transfusion independence, safety, and tolerability.

The median age of patients with AML was 74 years (range, 44-83) and 74.5 years (range, 44-85) in the FLT3-mutated and SF-mutated populations, respectively.1 Half of patients were male in the FLT3-mutated population compared with 65% in the SF-mutated group. The median bone marrow blast percentage was 33% (range, 18%-98%) and 27% (range, 5%-56%) in these respective groups. The majority of patients across both arms were White (83.3%; 85%), and both groups received a median of 2 prior lines of therapy (range, 1-2).

At the time of data cutoff, 1 of the 12 treated patients with a FLT3 mutation was still receiving treatment and had not yet reached their first response assessment. In the 20 treated patients with SF mutations, 2 were still undergoing treatment and pending for post-baseline marrow blast data, 2 discontinued treatment early due to an adverse effect (AE), and 1 discontinued due to progression.

In the overall safety population, 27.6% of patients experienced grade 3 or higher treatment-related AEs (TRAEs); of these, 22.8% were non-hematological. Common TRAEs reported in at least 1 patient included blood creatine phosphokinase increase (4.9%), platelet count decrease (4.9%), rhabdomyolysis (3.3%), anemia (2.4%), aspartate aminotransferase increase (2.4%), alanine aminotransferase increase (1.6%), dizziness (1.6%), febrile neutropenia (1.6%), lipase increase (1.6%), neutropenia (1.6%), neutrophil count decrease (1.6%), and syncope (1.6%).

“Enrollment in this trial is continuing at the RP2D of 300 mg twice a day [in the] phase 2 expansion cohort in patients [with] SF and FLT3 mutations and less than 3 prior lines of therapy,” investigators concluded.1

Disclosures: Dr Winer reports serving in a consulting or advisory role for Curis and Jazz Pharmaceuticals.


  1. Winer E, Verma A, Groepper S, et al. Preliminary safety, efficacy and molecular characterization of emavusertib (CA-4948) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) with FLT3 mutation (FLT3m). J Clin Oncol. 2024;42(16):6539. doi:10.1200/JCO.2024.42.16_suppl.6539
  2. Dose escalation/​ expansion study of CA-4948 as monotherapy in patients with AML or MDS. Updated March 11, 2024. Accessed June 10, 2024.
Related Videos
Bradley McGregor, MD, discusses findings from a phase 1b study of abemaciclib  in clear cell renal cell carcinoma.
Paolo Tarantino, MD
Adrienne G. Waks, MD,
Eric Winer, MD
Paolo Tarantino, MD
Joaquim Bellmunt, MD, PhD
Lakshmi Nayak, MD
Ana Christina Garrido-Castro, MD
Bradley McGregor, MD
Bradley McGregor, MD