Early Emavusertib Success in AML and MDS Continues to Build

The dual IRAK4 and FLT3 inhibitor emavusertib (CA-4948) has produced early signals of robust clinical activity in patients with relapsed/refractory acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes (MDS), and there is potential for the agent to exhibit enhanced efficacy in combination regimens, according to Eric S. Winer, MD.

The phase 1/2 TakeAim Leukemia trial (NCT04278768) is evaluating the efficacy and safety of emavusertib monotherapy in patients with relapsed/refractory AML and MDS. Preliminary findings in the subset of patients with FLT3-mutated AML who received emavusertib monotherapy at the recommended phase 2 dose of 300 mg twice daily (n = 7) demonstrated that the agent elicited best responses of complete response (n = 2), morphologic leukemia-free state (n = 1), stable disease (n = 2), progressive disease (n = 1), and not evaluable (n = 1).

“[Emavusertib is] an exciting drug in the sense that it [could work against] the targeted aspects of diseases and block levels of chemotherapy resistance as well,” Winer said.

In an interview with OncLive^®, Winer discussed how the unique mechanism of action of emavusertib strengthens its potential for use in the treatment of patients with AML and MDS, key preliminary findings with this agent in the TakeAim Leukemia trial, and future research directions with emavusertib in hematologic oncology.

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

OncLive: What was the rationale for initiating the TakeAim Leukemia trial?

Winer: [Patients with] AML, which [represent most of the patients] on the TakeAim Leukemia study—although it also includes patients with MDS—have a significant unmet need. Although overall survival [OS] in AML [has improved] with several different agents that have come about, such as venetoclax [Venclexta], FLT3 inhibitors, and IDH inhibitors, the reality is, the 5-year OS rate in the whole of [the AML population] is only approximately 28%. [This population] definitely fits into the unmet need category [where we need] to try to come up with better solutions and better drugs, [including] targeted agents that can improve longer-term survival.

What is the mechanism of action of emavusertib, and what makes this agent unique compared with others in the AML field?

Emavusertib is a novel agent because it’s both an IRAK4 inhibitor and a FLT3 inhibitor. We know about FLT3 inhibitors because we’ve got a couple approved drugs in that arena: gilteritinib [Xospata], midostaurin [Rydapt], and quizartinib [Vanflyta]. However, the IRAK4 aspect of [emavusertib] is novel. [Emavusertib] acts through a mechanism called the myddosome. It blocks MAPK downstream, and it also blocks NF-κB.

Interestingly, studies done with IRAK4 inhibition in AML found that there are a couple different isoforms of IRAK4. In particular, there’s a long isoform of IRAK4, which is highly prominent in AML, [present in approximately] 50% of patients with AML. This [knowledge] makes [IRAK4] an exciting target, which we can [use] to try to help block the proliferation [of AML] and gain better footholds in the treatment of patients with this disease.

How was TakeAim Leukemia designed?

TakeAim Leukemia had a dose-escalation design. There are 2 separate aspects to this trial. One was examining [patients with AML with] individual targeted mutations, and the other was evaluating [patients with] AML as a whole. The initial trial was a single-agent, dose-escalation [study] investigating a couple different dose levels [of emavusertib] to monitor toxicity, like in any other phase 1 trial, and then it moved toward a dose-expansion portion. We found that the 300 mg twice-daily dosing was a solid dose-expansion level.

Initially, [this trial included] 59 patients with AML and 33 [patients with] high-risk MDS. What we found—not surprisingly because [this finding] fits with IRAK4 and FLT3 inhibitor [mechanisms of emavusertib] work—is that the patients who experienced the best efficacy [with emavusertib] were those with mutations in spliceosomes or FLT3. We’re evaluating that patient population now [with emavusertib] as a single agent, but we’re also looking at expanding [emavusertib] in combinations as well.

What do the preliminary efficacy findings indicate about the potential for emavusertib in patients with AML or MDS?

In the AML population, particularly the [population with] FLT3-mutated disease, we’ve seen some other agents have good success in this [setting]. It’s been terrific to see that success. What’s been nice about emavusertib is it seems to work well in patients with FLT3 mutations, but also in those who have previously received FLT3 inhibitors. We’ve seen [responses in] patients [who are negative for] FLT3 mutations by polymerase chain reaction or next-generation sequencing, so we’re getting a nice, targeted effect. One of the thought processes behind this [efficacy] is that [emavusertib has] a different mechanism of action than just FLT3 inhibition, and it blocks a chemotherapy-resistant bypass mechanism, which has been seen in AML and MDS [and is also] expressed in solid tumors and lymphomas.

What safety concerns associated with emavusertib are investigators monitoring for during this trial?

In any type of phase 1 trial, we look for any type of safety signal. The main safety issues we were looking for were some aspects of cytopenias, but we didn’t see any dramatic problems with cytopenias. We also looked at issues with transaminase elevation, and we didn’t see that either.

One adverse effect we saw was a slight elevation in creatine phosphokinase, but we didn’t see significant increases in those levels, and we didn’t see levels where patients were developing rhabdomyolysis, which is the bigger concern when you see increases in creatine phosphokinase. When we saw those increases, we could mitigate them with dose reductions. With our current dosing scheme of 300 mg twice daily, we’ve done a nice job of preventing [creatine phosphokinase increases].

How might the findings from the TakeAim Leukemia trial, if positive, impact the management of AML and MDS?

It’s always intriguing and important to have [agents with] novel mechanisms of action that can be targeted and specific, such as [those that target] FLT3, [as well as agents that target mutations such as] IRAK4, which [need to be] a little more agnostic. It’s great that we see single-agent activity [with emavusertib] because we always want to see single-agent activity with these treatments.

The more exciting aspects [of this research] are going to be when we [investigate emavusertib] in combinations, because every drug we’ve brought forth in [AML in] the past decade has had modest effects as a single agent. [However, when they are included in] combinations, we see significant improvements in response and survival. That’s going to be the next step in investigating this drug.

It’s an exciting time to be in this field because when you look back 15 years ago, or even 20 years ago, we just had high-dose chemotherapy and low-dose chemotherapy, such as cytarabine. [We only had] conventional chemotherapies. With drugs such as emavusertib and others, we’re changing the way we think about how to treat leukemia with both a single-mutation targeted effect and with other combinations of small-molecule inhibitors. [These developments] make the field extraordinarily exciting in terms of what we’ll see in advances in the next 5 to 7 years.

Reference

Winer ES, Verma A, Groepper S, et al. Preliminary safety and efficacy of emavusertib (CA-4948) in acute myeloid leukemia patients with FLT3 mutation. Blood. 2023;142(suppl 1):2924. doi:10.1182/blood-2023-190007