Emavusertib Represents Safe, Manageable IRAK4 Inhibitor in FLT3- and Splicing Factor–Mutated AML

Treatment with emavusertib (previously CA-4948) demonstrated anti-leukemic activity and a manageable safety profile in patients with relapsed/refractory FLT3- and spliceosome-mutated acute myeloid leukemia (AML), according to data from the phase 1/2a TakeAim Leukemia trial (NCT04278768) which were presented in a poster session during the 2024 ASCO Annual Meeting.

In the ongoing, open-label trial, investigators evaluated 12 patients with FLT3-mutated AML, and of those treated with 300 mg of emavusertib twice daily, 3 experienced complete response (CR), 2 achieved a morphologic leukemia-free state (MLFS), and 1 demonstrated evidence of CR with partial hematologic recovery (CRh). Of the 15 evaluable patients with spliceosome-mutated disease, 1 achieved MLFS, 1 reached CR, and 2 experienced CRh/CR with incomplete count recovery (CRi).

“Overall, it’s a very promising drug and it is something that we will hopefully be able to move forward with to see better efficacy and better treatments for our patients,” lead study author Eric Winer, MD, explained of the agent in an interview with OncLive^®.

In the interview, Winer highlighted the utility of the IRAK4 inhibitor emavusertib in patients with FLT3- and spliceosome-mutated relapsed/refractory AML, discussed the safety and efficacy outcomes of the TakeAim Leukemia trial, and expanded on future research endeavors with emavusertib in combination therapies.

Winer is the clinical director of Adult Leukemia and an institute physician at Dana-Farber Cancer Institute; and an assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

OncLive: What is the mechanism of action of emavusertib, and how does it differ from other agents in this space?

Winer: There aren’t a lot of similar agents in this space because this is the first agent of its type. It is an IRAK4 inhibitor and IRAK4 inhibits the mechanism of how cells multiply, particularly in terms of spliceosomes, which is a very common mutation in myelodysplastic syndrome [MDS].

Furthermore, it has inhibition of FLT3, which is a known mutation that is very active in AML, and affects some other proteins, such as CLK1, CLK2, and CLK4.

What was the rationale for the TakeAim Leukemia trial?

The TakeAim Leukemia trial was [meant] to determine how IRAK4 inhibited and [facilitated] cell death in AML cells and high-risk MDS cells. Particularly, attention was paid to 2 groups, which is the FLT3 group and the spliceosome-mutated group.

What were some of the main findings from the TakeAim Leukemia trial?

The nice thing about the TakeAim Leukemia trial is that the results mirrored what we were expecting from the preclinical data and whenever we think about a new drug, we want the drug to have the effect that we expect. For example, we did see an effect across the board in terms of reduction of blast count in more than 50% of patients.

[This was] particularly [evident] in the FLT3-mutated and spliceosome-mutated group who had a significant effect in terms of responses and the reduction in blast [count]. It was nice that we were able to prove principle from what we were seeing, and prove an anti-leukemic effect, which will then allow us to move forward with other trials.

What were the key efficacy findings from the subset of patients with FLT3-mutated disease?

In FLT3-mutated disease, what was nice is that this IRAK4 inhibitor, emavusertib, inhibits both the FLT3 ITD mutation as well as the FLT3 TKD mutation. Half of the 12 patients who were treated fit into the overall response categories. We had 6 overall responses and we had 4 patients with CR and CRh. That shows that this [treatment provides] an on-target effect, and that we can see benefit for our patient population.

What was the safety profile of emavusertib in this population?

For our population emavusertib was very well tolerated. The average age of patients in this population was a little over 75 years old. We’re dealing with a relatively older and somewhat more frail population than a 40 year old, for example. We did see some low blood counts, but we see low blood counts with this disease, regardless.

There were a couple of patients who had an elevation in their creatine kinase, but that was something that when we stopped the drug the creatine kinase numbers normalized. We also saw a slight elevation in some patients’ liver function tests or transaminases. Again, when we stopped the drug we were able to restart the patients on the drug, either at the same dose or at a slightly lower dose with good efficacy and tolerance.

What did some of the additional correlative analyses from this trial show?

This analysis [evaluated whether] the drug had the effect that we wanted, [particularly] in [the population with] FLT3 and spliceosome mutations; that’s what we were able to see. [Encouragingly] we saw efficacy with the drug in patients with these mutations, which are very common in MDS and AML.

Are there any next steps planned for this research?

When we look at a drug, the first thing we want to know is if it is hitting its target and if it is effective. Now that we know it’s hitting its targets and is effective, the next step would be to ask if we can we look at this in combination with another therapy.

What’s nice about this drug is that not only does it seem to have its on-target effect, but we believe it will affect some of the breakthrough mechanisms responsible for relapse that we see with traditional chemotherapy. By adding this drug, we not only will have an on-target effect, but we’ll be able to block the breakthrough mechanism, leading to more effective therapy.

Overall, this [is a study] that gives us a lot of hope moving forward. The nice thing about this drug is that we’re not only seeing this drug being effective in leukemia. Another study that was presented at the 2024 ASCO Annual Meeting showed efficacy with emavusertib in combination with ibrutinib [Imbruvica] in primary central nervous system lymphoma, [suggesting that IRAK4] is another target that is going to be helpful in hematologic malignancies.

Reference

Winer ES, 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(suppl 16):6539. doi:10.1200/JCO.2024.42.16_suppl.6539