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.

“[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 

. “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.

“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 

. “The highest level of interest [with this agent] is for patients with AML [with]

 mutations or the specific spliceosome mutations

. 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 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.

“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 

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 

 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.

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 

-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).

At the June 12, 2023, data cutoff, 5 of 9 response-evaluable patients with 

-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 

 mutations, but also in those who have previously received FLT3 inhibitors,” Winer said. “We’ve seen [responses in] patients [who are negative for] 

 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 

-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.”

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

Parrondo RD, Iqbal M, Von Roemeling R, Von Roemeling C, Tun HW. IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies. 

. 2023;14:1239082. doi:10.3389/fimmu.2023.1239082

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

Winer ES, Verma A, Groepper S, et al. Preliminary safety and efficacy of emavusertib (CA-4948) in acute myeloid leukemia patients with 

. 2023;142(suppl 1):2924. doi:10.1182/blood-2023-190007

Articles

The TakeAim Leukemia trial aims to add emavusertib to the treatment paradigm of acute myeloid leukemia and high-risk myelodysplastic syndrome.

Emavusertib Progresses to Phase 2 Study in AML and MDS

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 

-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.

, 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.

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

: [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.

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 

. 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] 

-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 

 mutations, but also in those who have previously received FLT3 inhibitors. We’ve seen [responses in] patients [who are negative for] 

 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] 

, [as well as agents that target mutations such as] 

, 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.

Winer ES, Verma A, Groepper S, et al. Preliminary safety and efficacy of emavusertib (CA-4948) in acute myeloid leukemia patients with FLT3 mutation.

Eric S. Winer, MD, discusses the mechanism of action of emavusertib and preliminary findings from the TakeAim Leukemia trial in acute myeloid leukemia.



Early Emavusertib Success in AML and MDS Continues to Build 

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, sponsored by Curis, we had the pleasure of speaking with Alice Mims, MD, on the utility of the IRAK4 and FLT3 inhibitor emavusertib (previously CA-4948) in heavily pretreated patients with 

-mutated relapsed or refractory acute myeloid leukemia or myelodysplastic syndromes. Emavusertib is under evaluation in these patient populations in the phase 1/2a TakeAim Leukemia trial (NCT04278768).

Dr Mims is a medical oncologist and an associate professor in the Division of Hematology at The Ohio State University Comprehensive Cancer Center—James in Columbus.

In our exclusive interview, Dr Mims discussed the rationale for launching the phase 1/2a investigation, noting the potential implications of these findings thus far.

That’s all we have for today! Thank you for listening to this episode of 

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Podcasts

Dr Mims discusses the utility of emavusertib in acute myeloid leukemia and myelodysplastic syndrome and the rationale for the TakeAim Leukemia trial. 

Mims Expands on the Evaluation of Emavusertib in the TakeAim Leukemia Trial of AML and MDS

The IRAK-4 and FLT-3 inhibitor emavusertib (previously CA-4948) demonstrated a favorable safety profile and early signs of antitumor activity in heavily pretreated patients with relapsed or refractory acute myeloid leukemia (AML) harboring 

mutations, some of whom also expressed the spliceosome mutations

-mutated AML cohort (n = 10) in the phase 1/2a TakeAim Leukemia trial (NCT04278768) were presented at the

. Data from the dose-escalation portion of the study showed that 29.3% of patients in the safety population (n = 92) experienced treatment-related adverse effects (TRAEs) of grade 3 or greater, the majority of which were reversible and manageable. Grade 3 or greater treatment-emergent adverse effects occurred at a rate of 70% in the 

-mutated cohort; notably, no dose-limiting toxicities (DLTs) or myelosuppression were reported in these patients. Moreover, 5 of the 9 response-evaluable patients experienced bone marrow blast reduction of more than 90% compared with baseline. Mutational profiles suggest emavusertib’s potential disease-modifying activity in this patient population.

“It’s exciting that we’re starting to see responses [with emavusertib monotherapy] in these populations—especially as the agent has dual activity against different targets,” Mims, who is a medical oncologist, associate professor in the Division of Hematology, and director of Acute Leukemia Clinical Research at The Ohio State University Comprehensive Cancer Center—James, in Columbus, told 

®. “Seeing that there may be a potential targeted agent for patients with spliceosome mutations, when there’s no [drug specifically approved] for that population right now, is [also] exciting.”

The phase 2a dose-expansion portion of the trial is ongoing and is currently evaluating the recommended phase 2 dose (RP2D) of twice-daily 300 mg of emavusertib in patients with 2 or more prior lines of therapy. Preliminary analysis of 7 patients with 

-mutated AML demonstrated 2 achieved complete responses (CR), 2 achieved stable disease, 1 achieved a morphologic leukemia-free state, and 1 experienced disease progression with the agent.

In the interview, Mims discussed the rationale for specifically evaluating emavusertib in patients with AML and either 

or specific spliceosome mutations, reported safety and early efficacy findings from the dose-escalation/dose-expansion portions of the phase 1 study, and highlighted future research avenues for assessing the potential benefit of emavusertib in combination regimens or for patients harboring other spliceosome mutations.

: What is the mechanism of action of emavusertib, and why was this agent specifically evaluated in patients with 

-mutant AML and high-risk myelodysplastic syndrome (MDS)?

: Emavusertib is a small molecule kinase inhibitor, and it is multitargeted. It showed preclinical activity against IRAK4 and FLT3, as well as Cdc2-like kinases, which are [targets] of interest these days.

The highest level of interest [in this agent] is for patients with AML [harboring]

 mutations or the specific spliceosome mutations

. The study is also looking at patients with high-risk MDS, specifically in those with the same spliceosome mutations. The reason [for this] is that IRAK4 is upregulated during anti-FLT3 or other cytotoxic therapies, so it could drive resistance pathways for patients who are on FLT3 inhibitors. It’s important to look at that and [see if emavusertib] is something that could be used initially in combination, as opposed to current FLT3 inhibitors [alone]. Patients with spliceosome mutations have an excess of IRAK4 ligand, and that enhances the toll-like receptor pathway, which is frequently dysregulated in AML.

What was the design of the phase 1/2 study? What patients were eligible for enrollment?

This is a phase 1 dose-escalation, phase 2 dose-expansion study. When the study first started, it was for all-comers, [comprising] patients 18 years of age and older who had relapsed/refractory AML or higher-risk MDS that was not responsive to hypomethylating agents [HMAs].

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 

mutations, [investigators] wanted to be sure that they had previously received a FLT3 inhibitor, since a few of those are FDA approved in different settings.

What were the primary end points of the study?

For the phase 1 portion of the study, [the primary end points were] safety and tolerability in patient populations, [as well as] identifying the maximum tolerated dose and RP2D. The primary end point for the dose-expansion phase 2a portion is anticancer activity in those specific AML and MDS populations. For the AML [population], [investigators are] specifically looking at the proportion of patients who achieve a CR or a CR with hematologic improvement. For the high-risk MDS population, they’re looking at overall response rate, which is defined as a CR after partial remission.

What initial efficacy findings were reported from the study at the 2023 ASH Annual Meeting?

[In the presentation, investigators] focused on responses in patients with relapsed/refractory AML and

 mutations. [Eleven] patients were included in the dose-escalation portion, [9 of whom were response evaluable]. Nine of the patients had 

TKD mutation. Two of the patients with an 

mutation. These patients had been heavily pretreated.

[Investigators] saw reductions in blast count for those patients. Enrollment in the dose expansion for the phase 2a portion of the study has started, and they’re moving forward with a 300-mg twice-a-day oral dose. They’ve looked at patients with 

 mutations; 2 of these patients have [achieved] CR, and 1 has [achieved] a morphologic leukemia-free state. The interesting thing to note is that the patients with the

ITD mutations who [achieved] CRs also had undetectable status of their 

ITD mutations and minimal residual disease–negative status.

The drug seems to be overall well tolerated. There have not been any DLTs in those 10 patients presented and no dose-limiting myelosuppression was noted. TRAEs have been seen. Two studies are currently looking at this agent in different populations, and [the most common] adverse effects [AEs] occurring in more than 10% of the patients treated would be creatine phosphokinase [CPK] increases, nausea, dizziness, fatigue, diarrhea, and alanine transaminase level increases. One AE of special interest is rhabdomyolysis. Evidence of this [was seen] in preclinical animal models, so they’re following [this AE] along with CPK levels. From my understanding, there have not been any clinically significant rhabdomyolysis AEs reported in the study thus far. There may be some laboratory CPK elevation, but nothing that was not reversible for the patient.

Based on these data, what next steps are planned for research with emavusertib within the field of hematologic malignancies?

[Future research] could look at [whether] combination regimens [with] emavusertib [and] either intensive induction, triplet therapy, or venetoclax [Venclexta] and an HMA could be tolerated. Looking at it in the up-front setting would be exciting, as well.

There’s also some discussion and interest from investigators [in evaluating this agent in patients with] other spliceosome mutations that are not included [in the study], and [identifying whether] those could also be part of the eligibility criteria. We’ll see whether that moves forward or not. It’ll be important to see how things develop as the study moves forward in the phase 2 dose expansion.

Alice Mims, MD, discusses the toxicity profile and initial efficacy of emavusertib in heavily pretreated, FLT3-mutated relapsed/refractory AML.  

Emavusertib Demonstrates Safety, Early Antitumor Activity in Select Patients With FLT3-Mutant R/R AML

Dr Nowakowski on the Use of Emavusertib in Relapsed/Refractory Hematologic Malignancies

Grzegorz S. Nowakowski, MD, consultant, professor, vice chair, Oncology and Medicine, Division of Hematology, deputy director, Mayo Clinic Comprehensive Cancer Center for Clinical Research, discusses findings from the ongoing phase 1/2 TakeAim Lymphoma trial (NCT03328078) of emavusertib (previously CA-4948) in combination with ibrutinib (imbruvica) in patients with relapsed/refractory hematologic malignancies.

The multicenter, open-label, dose-escalation and -expansion trial is evaluating the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the orally administered, novel IRAK4 inhibitor emavusertib in combination with ibrutinib. Findings from this trial were 

In the initial phase of the study, the recommended phase 2 dose of emavusertib monotherapy was identified as 300 mg twice daily and was tolerated well, Nowakowski says. The combination involving the BTK inhibitor ibrutinib evaluated emavusertib at 2 dose levels: 100 mg twice daily and 200 mg twice daily, alongside the standard 560-mg daily dosage of ibrutinib, with a 28-day cycle duration, he explains. Notably, the study focused on patients previously exposed to BTK inhibitors, Nowakowski notes.

The primary efficacy results yielded promising outcomes, with 19 evaluable patients undergoing response evaluation. Among these patients, 5 complete responses (CRs) were observed, 2 occurring in patients with mantle cell lymphoma and 3 occurring in patients with primary central nervous system lymphoma (PCNSL), he expands. Notably, all patients with PCNSL had prior exposure to BTK inhibitors, providing evidence that the preclinically observed synergy of emavusertib plus a BTK inhibitor is translating into clinical success, he emphasizes.

Nowakowski goes on to say that the aspect of these data generating the highest level of excitement revolves around the challenging-to-treat PCNSL patient population, especially cases resistant to chemotherapy, which have limited treatment options. The combination of the oral agents emavusertib and ibrutinib, which has produced CRs, is a notable advancement, he states. Although ibrutinib has been known to drive responses in PCNSL, these responses were transient and accompanied by eventual resistance, Nowakowski says. The addition of emavusertib to ibrutinib in this patient population led to CRs, validating the preclinical hypothesis that the simultaneous inhibition of BTK and IRAK4 is critical for suppressing B-cell proliferation and survival, he concludes.

Videos

Grzegorz S. Nowakowski, MD, discusses data from the phase 1/2 TakeAim Lymphoma trial of emavusertib plus ibrutinib in patients with hematologic malignancies.

Dr Kadia on Targeting the IRAK4 Pathway in AML

Tapan M. Kadia, MD, professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discusses targeting the IRAK4 pathway in patients with acute myeloid leukemia (AML) and highlights the importance of utilizing targeted therapies in the treatment of patients with hematologic malignancies.

The IRAK4 pathway, initially targeted in the management of myelodysplastic syndrome, is now gaining traction in AML due to its analogous nature, Kadia begins. Although studies in AML are in early stages, their potential impact remains promising, as the IRAK4 pathway contains a loop of inflammatory cytokines, he states. The optimal targeting of this pathway in patients with newly diagnosed or relapsed AML is still unfolding, and ongoing studies aim to provide insights into the efficacy of IRAK4-targeted agents, Kadia explains. Overall, when anticipating the future of AML management, targeted therapies emerge as pivotal players, he notes.

Targeted therapy benefits patients with AML because it is generally less intense and toxic than traditional therapies, Kadia says. One such therapy is the class of IDH1 inhibitors, Kadia continues. A strategic combination of lower intensity therapy with these inhibitors yields response rates comparable, if not superior, to those observed with traditional intensive chemotherapy, he emphasizes. To harness the potential of targeted therapies, comprehensive characterization of leukemia at the outset through next-generation sequencing is imperative, Kadia imparts.

Understanding mutations and cytogenetics informs the selection of therapies tailored to specific AML subsets. FLT3 inhibitors, such as midostaurin (Rydapt) and quizartinib (Vanflyta), showcase advancements in frontline AML management, providing new treatment options for patients, Kadia expands. Exploring the extended use of quizartinib reveals promising results, especially for patients with minimal residual disease–positive disease, he explains. The evolving landscape emphasizes a dynamic approach, continuously assessing the disease from diagnosis, adapting therapies to its changing nature, and investigating whether lower intensity treatment options can match the efficacy of intensive chemotherapy in newly diagnosed patients, Kadia states.

Although low-intensity therapy is currently reserved for older or unfit patients, ongoing trials are exploring its effectiveness compared with intensive chemotherapy in various patient populations, he says. Despite the current standard of care favoring intensive chemotherapy, the tailored approach recognizes exceptions, such as younger patients with 

 mutations or high-risk disease, in whom low-intensity therapy is deemed appropriate, Kadia concludes.

Tapan M. Kadia, MD, discusses targeting the IRAK4 pathway in patients with acute myeloid leukemia and highlights the importance of utilizing targeted therapies in the treatment of patients with hematologic malignancies.


Dr Stein on the Development of Targeted Therapies in Splicing Mutant Hematologic Malignancies

Eytan M. Stein, MD, director, Program for Drug Development in Leukemia, chief, Leukemia Service, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses the ongoing development and investigation of therapies targeting splicing mutations in hematologic malignancies.

The investigational oral IRAK4 inhibitor emavusertib (formerly CA-4948) is currently being investigated as a targeted therapy for patients with hematologic malignancies, such as acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), whose disease harbors a spliceosome or 

 mutation, Stein begins. IRAK4, a critical component in the pathogenesis of splicing-mutant AML, is selectively and reversibly inhibited by emavusertib, he explains. This small molecule demonstrates favorable pharmacological characteristics, including oral bioavailability, moderate plasma binding, stability, and rapid absorption and clearance.

This novel agent is currently being evaluated in the phase 1/2 TakeAim Leukemia trial (NCT04278768) both as a monotherapy and in combination with azacitidine and venetoclax (Venclexta) in patients with relapsed/refractory acute AML or high-risk MDS. Initial results showed a significant reduction in blast count irrespective of dose level, mutation status, or number of prior lines of treatment. Notably, 2 of the 3 evaluable patients with 

mutations treated with the recommended phase 2 dose of 300 mg twice-daily achieved a complete response (CR), and 2 of 3 patients with a spliceosome mutation achieved a CR with partial hematologic recovery.

Despite advancements in the investigation of emavusertibas a potential therapeutic agent in this population, questions remain about its specificity for splicing mutations and broader applicability beyond this specific genetic subset, Stein notes.

In addition to emavusertib, there is growing interest in a novel class of drugs known as CLK inhibitors, Stein continues. These agents inhibit CLK protein kinases involved in pre-mRNA splicing to reduce cell growth and promote cell death. Preliminary data from a phase 1/2 study in Japan (JapicCTI-184188) have shown a promising response rate with the first-in-class CLK inhibitor CTX-712 in a small cohort of patients with MDS. These CLK inhibitors may exhibit activity specific to patients with splicing factor mutations, hinting at a potential avenue for future therapeutic developments, Stein concludes.

Editor's Note: Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.

Eytan M. Stein, MD, discusses the ongoing development and investigation of therapies targeting splicing mutations in hematologic malignancies.
 