Emavusertib Holds Potential for Combination Therapies in AML/MDS

Data emerging from the phase 1/2 TakeAim Leukemia trial (NCT04278768) evaluating emavusertib (CA-4948) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) have opened the door for potential combination therapies with the agent, according to Guillermo Garcia-Manero, MD.

“The question is going to be whether [emavusertib] will be a doublet or a triplet, and that will depend very much on [results from the phase 3] Verona trial [NCT04401748],” Garcia-Manero said in an interview with OncLive®. “There is a big study [evaluating] azacitidine [Vidaza] with or without venetoclax [Venclexta] in patients with previously untreated, high-risk MDS. If that's a positive study, then the next generation of trials will be triplets, [meaning] a hypomethylating agent [HMA] plus venetoclax and, hopefully, emavusertib.”

Findings from FLT3-mutated AML cohort (n = 11) in the TakeAim Leukemia trial presented at the 2024 ASCO Annual Meeting demonstrated that 3 patients treated with emavusertib achieved a complete response (CR), 1 had a CR with partial hematologic recovery (CRh), and 2 experienced a morphological leukemia-free state (MLFS). In a cohort of patients with AML harboring splicing factor mutations (n = 15), 1 patient had a CR, 2 had a CRh/CR with incomplete count recovery (CRi), and 1 achieved MLFS.

Updated data presented at the 2024 ASH Annual Meeting, show that there were 10 objective responses out of 19 response-evaluable patients with AML.2 Of these objective responses, 6 patients had a CRs, 2 had a CRi/CRh, and 2 had MLFS.

During the interview, Garcia-Manero discussed the mechanism of action of emavusertib, the rationale for investigating the drug in AML and MDS, the potential use of emavusertib in combination therapies, and its effect on the AML and MDS treatment paradigms.

Garcia-Manero is a professor, chief of the Section of MDS, deputy chair of Translational Research, and fellowship program director in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center.

OncLive: What is the unique mechanism of action of emavusertib?

Garcia-Manero: In leukemia, in general, there is a pathway that seems to be overactivated in a significant fraction of patients with MDS and some with AML. [This pathway] is downstream of toll-like receptor activation and is mediated by these enzymes known as IRAK and these are like signaling modules that then feed downstream to NF-κB deactivation, and then they produce different cytokines. These are normal processes of innate immune responses, but they seem to be barely engaged in patients with different leukemias.

Of interest, [overactivation of this pathway] is not unique to myeloid disorders. You can also see these in B-cell malignancies. IRAK probably could be a target for different diseases. We got interested in this some time ago because, through a number of experiments, we found that this pathway was overactivated in MDS, particularly [in patients] with lower-risk disease. We've been trying to develop drugs against this particular pathway. Therefore, we've been working with our colleagues now for quite [some] time in trying to develop one of these inhibitors.

It turns out that [emavusertib] is not a super-specific IRAK inhibitor; it also hits other kinases. FLT3 can be a target of this particular compound, which makes it attractive because it could also have a role in AML [harboring] FLT3 mutations. In addition, there are some data suggesting that there may be different splice isoforms of IRAK—what they call long vs short. There has been some data suggesting that perhaps there may be different response rates or sensitivities to this class of IRAK inhibitors, depending on the isoform that is engaged.

What is the rationale for investigating this type of inhibition within MDS and AML?

We have developed a number of clinical trials for high-risk MDS and AML targeting different splice isoforms, and in AML [specifically], focusing on FLT3 mutation status. What we have seen both in MDS and AML is that there is significant clinical activity with [emavusertib] as a single agent.

At the 2024 ASH Annual Meeting, there was another presentation on the AML experience, and also a poster with the MDS experience. We've been looking at perhaps shorter schedules of this drug—perhaps 7 to 14 days of emavusertib—as opposed to 21 days or every day of the cycle, because perhaps the liability of this compound could [cause] too much myelosuppression with daily exposure. Remember: FLT3 is normal for hematopoiesis.

The data in FLT3-mutated disease is quite significant with a high rate of responses. The [next] question here is, ‘How do we take a drug like this in a disease [such as AML] that is very well covered with many other FLT3 inhibitors?’ In MDS, this agent is quite exciting because we probably need to move it [to the] up-front [setting]. We have seen significant activity with 7 and 14 days of [treatment with] this compound. The toxicity profile is quite acceptable both in MDS and AML.

We're trying to think about the next steps in terms of combinations. Should we combine this agent with a HMA? What about venetoclax [Venclexta]? What would be the next type of study? We're looking for the results of the frontline VERONA trial with venetoclax [plus azacitidine] to guide us in terms of the design of the next study. As we speak, we're actually completing 7- and 14-day schedules of this drug.

In summary, these are active compounds targeting a very important pathway in myeloid and lymphoid leukemias. Although I don't have experience in lymphoid diseases, I think the drugs will [ultimately] have to be combined, and these are going to be part of our armamentarium.

What do the preliminary safety data look like and how might emavusertib be used in combination therapies?

Early in the development of these compounds, there was a question on rhabdomyolysis. I am not sure about the attribution of that particular toxicity, but [this is] a severe toxicity as we treat patients with very advanced leukemias. This was reviewed extensively by the FDA and led to a pause of the study we reopened, and, as far as I know, we have not really seen that toxicity.

What you will see is myelosuppression, and that's why finding the right dose schedule for this drug is so important. At the end of the day, FLT3 is something that we need for hematopoiesis. If you hit it too hard, then you will see myelosuppression, and we’ve seen that, for instance, with other FLT3 inhibitors. Therefore, we need to find the right dose and schedule that will allow [emavusertib] to be combined with some of the other compounds.

If data continue to be positive for emavusertib, either alone or in a combination regimen, what could this mean for the treatment paradigm within MDS and AML?

With MDS, we think about the first-line and second-line [settings]. The second-line is difficult. Is there HMA failure? I don't [currently] have enough in-depth information from the duration of responses and impact on survival to say whether this drug will be [viable as] a single agent [after] HMA failure. That would be amazing because an oral compound with a good toxicity profile could be really important for patients with second-line disease after a HMA.

If the VERONA trial is negative, that will open the doors to a doublet with a HMA [azacitidine] plus emavusertib. However, we don't have these data yet—that will be the next step. Hopefully, [emavusertib could have a role as] a single agent in the second line and maybe in combination, either as doublet or triplet, up-front.

In AML, with the approval of so many FLT3 inhibitors, we’re looking at a very distant line of exposure. We should also explore these drugs outside the context of FLT3-mutated disease.

We are almost ready to conclude a large, well-done phase 1 trial where we tried to figure out the dose schedule. That is [what is] going to guide us in terms of [treatment] combinations, whether it’s in FLT3-mutated or -unmutated [AML] or in MDS [in the] frontline [and] second-line settings. We just need to get to the finish line with the study and understand the proper dose because these are very powerful compounds.

References

1. 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
2. Curis Announces Additional Data from TakeAim Leukemia Study. News Release. Curis. December 10, 2024. Accessed January 27, 2025. https://investors.curis.com/2024-12-10-Curis-Announces-Additional-Data-from-TakeAim-Leukemia-Study