Eric S. Winer, MD, is clinical director of Adult Leukemia at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School.

Dr Winer on the Efficacy of Emavusertib in AML With FLT3 and Spliceosome Factor Mutations

“Emavusertib may be able to not just hit the bypass mechanisms for the previous diseases, but may have higher efficacy compared with the other FLT3 inhibitors that patients were already refractory to.”

Eric S. Winer, MD, clinical director, Adult Leukemia, Dana-Farber Cancer Institute; and assistant professor, medicine, Harvard Medical School, discusses top data from the ongoing phase 1/2 TakeAim Leukemia trial (NCT04278768) investigating the oral small molecule IRAK4 inhibitor emavusertib (CA-4948) in patients with relapsed/refractory acute myeloid leukemia (AML) harboring 

Of 19 evaluable patients with relapsed/refractory 

-mutated AML who had received 2 or fewer prior lines of therapy and received treatment with emavusertib at the recommended phase 2 dose of 300 mg twice daily, 6 patients had a complete remission (CR), 2 had a CR with either a CR with incomplete hematological recovery (CRi) or a partial hematological recovery, and 2 had morphologic leukemia-free state. These data further highlight the efficacy of emavusertib monotherapy, Winer says. Notably, 2 patients who achieved a CR and a CRi, respectively, subsequently underwent allogeneic stem cell transplantation.

A key finding from the trial was that most patients with 

-mutated AML had previously received FLT3 inhibitors, such as midostaurin (Rydapt) or gilteritinib (Xospata), many of whom still responded to emavusertib, Winer emphasizes. This suggests that emavusertib may effectively overcome resistance mechanisms associated with previous FLT3 inhibitors and may exhibit higher efficacy in this refractory population, he explains.

Patients with spliceosome factor mutations also achieved clinical responses with emavusertib, although its efficacy was less pronounced than in the cohort of patients with 

 mutations, Winer notes. Responses, including cCRs, were also observed in the spliceosome factor mutation subgroup, Winer states. Most of these patients had prior exposure to hypomethylating agents plus venetoclax (Venclexta), indicating that emavusertib may provide therapeutic benefits even in heavily pretreated populations, he concludes.

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Eric S. Winer, MD, discusses the efficacy of emavusertib in patients with relapsed/refractory AML harboring FLT3 and/or spliceosome factor mutations.

Dr Winer on the Rationale for the TakeAim Leukemia Trial in Mutated AML

Eric Winer, MD, clinical director, Adult Leukemia, institute physician, Dana-Farber Cancer Institute; assistant professor, medicine, Harvard Medical School, discusses 

the phase 1/2a TakeAim Leukemia trial (NCT04278768)

 investigating emavusertib (previously CA-4948) in patients with relapsed or refractory 

- and spliceosome-mutated acute myeloid leukemia (AML), as well as key efficacy findings from this study.

Notably, data from the investigation were presented at the 

. The TakeAim Leukemia trial was designed to determine the effectiveness of IRAK4 inhibition in promoting cell death in AML cells and high-risk myelodysplastic syndrome cells, Eric begins. This trial focused on 2 patient populations: those with 

 mutations and those with spliceosome mutations, he states. Treatment with emavusertib in patients with mutated AML reportedly demonstrated anti-leukemic activity and exhibited a manageable safety profile. The encouraging aspect of the TakeAim Leukemia trial is that its results aligned with expectations based on preclinical data, demonstrating that the drug performed as anticipated, Winer reports.

In practical terms, more than 50% of patients experienced a reduction in blast counts, with significant responses observed in the 

-mutated and spliceosome-mutated groups, Winer expands. This finding confirmed the study’s hypothesis and demonstrated a clear antileukemic effect with the agent, paving the way for further trials, he states. Additionally, in the 

-mutated disease group, the IRAK4 inhibitor was effective against both 

 ITD and TKD mutations. Among the 12 patients treated within the 

-mutated subgroup, 6 patients experienced responses, and 4 patients achieved complete remission (CR) or CR with incomplete blood count recovery, Winer emphasizes.

These results illustrate a targeted effect of the IRAK4 inhibitor, highlighting its potential benefit for patients with specific genetic mutations, he says. The trial’s success in proving the mechanism of action and efficacy of emavusertib offers promising implications for future therapeutic strategies and trials, Winer concludes.

Eric Winer, MD, discusses the rationale for the phase 1/2a TakeAim Leukemia trial of emavusertib in patients with R/R FLT3- and spliceosome-mutated AML.

Eric Stephen Winer, MD, assistant professor of medicine, Harvard Medical School, Dana-Farber Cancer Institute, discusses the FDA approval of ivosidenib (Tibsovo) in acute myeloid leukemia (AML).

May 2, 2019, the FDA approved a supplemental new drug application (sNDA) for ivosidenib as monotherapy for the frontline treatment of adult patients with 

-mutant AML, as detected by an FDA-approved test, who are ≥75 years old or are ineligible to receive intensive chemotherapy. Data from a phase I trial served as the basis for the approval. In the trial, ivosidenib induced a 28.6% (95% CI, 13.2-48.7) complete response (CR) rate and a CR plus CR with partial hematologic recovery (CRh) rate of 42.9% (95% CI, 24.5-62.8). The median durations of CR and CR+CRh were not estimable, and 41.7% (n = 5) of patients who achieved CR/CRh remain on ivosidenib as of the data cutoff.

This approval brings yet another targeted treatment option with significant benefit to patients with 

Eric Stephen Winer, MD, assistant professor of medicine, Harvard Medical School, Dana-Farber Cancer Institute, discusses the FDA approval of ivosidenib in acute myeloid leukemia (AML).

Eric S. Winer, MD

Articles

Dr Winer on the Efficacy of Emavusertib in AML With FLT3 and Spliceosome Factor Mutations

Dr Winer on the Rationale for the TakeAim Leukemia Trial in Mutated AML

Dr. Winer Discusses the FDA Approval of Ivosidenib in AML