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 FLT3 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 FLT3mutations 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.

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