Emavusertib Progresses to Phase 2 Study in AML and MDS

Eric S. Winer, MD

With the initiation of the phase 1/2 TakeAim Leukemia trial (NCT04278768), investigators are hoping to add a multitargeted agent to the treatment paradigm of both acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), disease settings where additional effective therapies are still needed.¹

“[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,” Eric S. Winer, MD, 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, said in an interview with OncologyLive. “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] 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.”

TakeAim Leukemia is examining the investigational agent emavusertib (CA-4948). In preclinical study, emavusertib demonstrated potent inhibition of toll-like receptor signaling, subsequently resulting in proinflammatory and cellular proliferation pathways in B-cell non-Hodgkin lymphoma (NHL) and myeloid malignancies. The agent displayed antitumor activity and an acceptable toxicity profile in mouse models of NHL and AML.²

“Emavusertib is a small molecule kinase inhibitor, and it is multitargeted. It showed preclinical activity against IRAK4, FLT3, and Cdc2-like kinases, which are [targets] of interest,” Alice S. Mims, MD, medical oncologist, assistant professor in the Division of Hematology, and director of Acute Leukemia Clinical Research at The Ohio State University Comprehensive Cancer Center—James, in Columbus, said in an interview with OncologyLive. “The highest level of interest [with this agent] is for patients with AML [with] FLT3 mutations or the specific spliceosome mutations U2AF1 and SF3B1. The study is also looking at patients with high-risk MDS, specifically in those with the same spliceosome mutations. The reason is that IRAK4 is upregulated during [the administration of] anti-FLT3 or other cytotoxic therapies, so it could drive resistance pathways for patients who are on FLT3 inhibitors.”

TakeAim Leukemia Study Design

TakeAim Leukemia is a multicenter, open-label dose escalation and expansion study of emavusertib in adult patients with AML or high-risk MDS. Eligible patients must 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. Those with active central nervous system disease, active advanced malignant solid tumors, and those who have received any systemic anticancer therapy within 3 weeks prior to starting treatment with emavusertib will be excluded from enrollment.¹

“When the study first started, it was for all-comers, [consisting of] patients 18 years of age and older who had relapsed/refractory AML or higher-risk MDS that was not responsive to hypomethylating agents [HMAs],” Mims noted. “Over time, the study was amended to just look at those specific AML populations mentioned above, as well as the MDS populations. [The study was] also limited to patients who had not received more than 2 lines of prior therapy. For the AML patients with FLT3 mutations, [investigators] wanted to be sure that they had previously received a FLT3 inhibitor, since a few of those [agents] are FDA approved in different settings.”

The dose escalation phase 1 and 1b portions will follow a 3 + 3 design; phase 1 will examine emavusertib monotherapy and phase 1b will examine emavusertib in combination with azacytidine for treatment-naïve patients with high-risk MDS or with venetoclax in patients with relapsed/refractory AML or high-risk MDS. Once the recommended phase 2 dose (RP2D) is determined, the phase 2 dose expansion will consist of 3 cohorts:relapsed/refractory AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor; relapsed/refractory AML with spliceosome mutations of SF3B1 or U2AF1; and relapsed/refractory high-risk MDS with spliceosome mutations of SF3B1 or U2AF1.

Emavusertib was administered at a starting dose of 200 mg twice daily on each day of a 28-day cycle in phase 1; in phase 1b the agent will be given for 21 days of each 28-day cycle. Oral venetoclax will be given at a dose of 100 mg at the same time daily with a 3-day ramp-up to 400 mg for 21 days of the 28-day cycle.

The primary end point of the phase 1 portion is determining the maximum tolerated dose (MTD) and RP2D of emavusertib monotherapy in patients with AML, intermediate high-risk and high-risk MDS. The primary end point of the phase 1b portion is determining the MTD and RP2D of emavusertib plus azacytidine for treatment-naive patients with high-risk MDS or in combination with venetoclax in patients with relapsed/refractory AML or high-risk MDS. In the phase 2a portion––emavusertib monotherapy expansion––the primary end point is response rate. Secondary end points in both phase 1 portions include pharmacokinetics, clinical response, and safety; secondary end points in phase 2 include duration of response, time to response, transfusion independence rate, and OS.

Preliminary Findings Demonstrate Efficacy, Tolerability of Emavusertib

In July 2023, the FDA removed the partial clinical hold on TakeAim Leukemia, which had been in place since April 2022. In August 2022, the FDA notified the developer of emavusertib that it may resume enrollment of patients in the monotherapy dose-finding phase. Also in July 2023, it was announced that the RP2D of emavusertib monotherapy was 300 mg twice daily for patients with AML or MDS.³

During the 65th American Society of Hematology Annual Meeting & Exposition (ASH 2023), which took place in December in San Diego, California, investigators presented preliminary efficacy findings from the FLT3-mutated AML cohort (n = 11) of TakeAim Leukemia and updated safety findings from the overall population (n = 92). The median age was 78 years (range, 61-87) and 74 years (range, 32-88), respectively. The median number of prior lines of therapy was 2 in both groups and the respective median platelet counts were 21 x 103/mm3 (range, 1-38) and 25.5 x 103/mm3 (range, 1-275).⁴

At the June 12, 2023, data cutoff, 5 of 9 response-evaluable patients with FLT3-mutated relapsed/refractory AML achieved a greater than 90% bone marrow blast reduction compared with baseline. Moreover, patients in this disease setting treated at the 300 mg dose level (n = 7) achieved a complete response (CR; n = 2), stable disease (n = 2), disease progression (n = 1), and morphologic leukemia-free state (n = 1); 1 patient in this group was not evaluable for response. The 2 patients who experienced CRs had blast count reductions of 99% and 100%, and had treatment durations of 213 and 225 days, respectively; the patient who achieved a morphologic leukemia-free state had a blast count reduction of 100% and a treatment duration of 134 days.

“It’s been terrific to see the success; what’s nice about emavusertib is it seems to work well in patients with FLT3 mutations, but also in those who have previously received FLT3 inhibitors,” Winer said. “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, [mult]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.”

In the safety population, patients treated at all dose levels experienced grade 3 or higher treatment-related adverse effects (TRAEs) at a rate of 29.3%. Grade 3 or higher TRAEs occurring in more than 1 patient consisted of decreased platelet count (5.4%), increased blood creatine phosphokinase levels (3.3%), decreased neutrophil count (3.3%), increased alanine aminotransferase (2.2%), anemia (2.2%), increased lipase (2.2%), neutropenia (2.2%), and syncope (2.2%). Notably, no dose-limiting myelosuppression occurred.

Study authors concluded that emavusertib displayed an acceptable and manageable safety profile in relapsed/refractory AML and high-risk MDS. They also noted that changes in mutational profiles are suggestive of the disease-modifying activity of the agent and that emavusertib demonstrated anti-tumor activity in patients with FLT3-mutated disease, including those who progressed on a prior FLT3 inhibitor. Enrollment in the trial was ongoing at the RP2D in the phase 2 expansion cohort in patients with 2 or fewer prior therapies at the time of ASH 2023.

“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,” Winer said in conclusion. “[However, when they are included in] combinations, we see significant improvements in response and survival. It’s an exciting time to be in this field because when you look back 15 or 20 years ago, we just had high- and low-dose chemotherapy. With drugs such as emavusertib, we’re changing the way we think about treating leukemia with both a single-mutation targeted effect and with other combinations of small-molecule inhibitors. [Advances such as these] make the field extraordinarily exciting in terms of what we’ll see in the next 5 to 7 years.”

References

1. Dose escalation/​ expansion study of CA-4948 as monotherapy in patients with AML or MDS. ClinicalTrials.gov. Updated March 11, 2024. Accessed March 12, 2024. https://www.clinicaltrials.gov/study/NCT04278768
2. Parrondo RD, Iqbal M, Von Roemeling R, Von Roemeling C, Tun HW. IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies. Front Immunol. 2023;14:1239082. doi:10.3389/fimmu.2023.1239082
3. FDA removes partial clinical hold on TakeAim Leukemia study RP2D established at 300 mg BID. News release. Curis, Inc. July 6, 2023. Accessed March 6, 2024. https://www.prnewswire.com/news-releases/fda-removes-partial-clinical-hold-on-takeaim-leukemia-study-rp2d-established-at-300-mg-bid-301870902.html
4. 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