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.

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

Eytan M. Stein, MD, director, Program for Drug Development in Leukemia, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses the phase 2 SELECT-AML-1 trial (NCT04905407) in patients with newly diagnosed acute myeloid leukemia (AML).

The phase 2 SELECT-AML-1 trial is examining the utilization of tamibarotene (Amnolake) plus venetoclax (Venclexta) and azacitidine (Vidaza) in patients with retinoic acid receptor alpha (RARA)–positive AML who are unlikely to tolerate standard intensive chemotherapy as a frontline treatment.

The first part of the trial will examine the safety of combining tamibarotene with venetoclax and azacitidine, followed by the second part of the study where patients will be randomized 1:1 to receive venetoclax and azacitidine with or without tamibarotene, Stein explains.

Notably, a subset of patients receiving venetoclax and azacitidine alone will be permitted to cross over to receive tamibarotene with venetoclax and azacitidine if they fail on treatment, Stein continues. The primary end points of SELECT-AML-1 will be complete remission rates and overall response rates, and exploratory end points included pharmacokinetics and additional safety, Stein concludes.

Eytan M. Stein, MD, discusses the phase 2 SELECT-AML-1 trial in patients with newly diagnosed acute myeloid leukemia.


Dr. Stein on the SELECT-AML-1 Trial in Newly Diagnosed AML

Eytan Stein, MD, attending physician in the leukemia service at Memorial Sloan Kettering Cancer Center, discusses new data from a phase I study exploring the oral IDH2 inhibitor AG-221 in patients with advanced hematologic malignancies, primarily acute myelogenous leukemia (AML) and myelodysplastic syndrome.

At the time of the data cut-off, 45 patients with 

 mutations were analyzed for response. Overall, by investigator-accessed criteria, 56% of patients responded to therapy, Stein explained.

Responses were comprised of complete remissions (CR; n = 6), CR with incomplete platelet recovery (n = 4), marrow CR (n = 4), CR with incomplete hematologic recovery (n = 1), and partial remissions (n = 10). Responses were durable and lasted for 3 months or longer in the majority of patients.

These findings were from an interim analysis of a phase I trial, Stein emphasized. However, if these results are confirmed in larger trials, it could represent a quantum leap over previous treatments for patients with AML that could potentially lead to durable remissions.

View more from the 2014 ASH Annual Meeting

Eytan Stein, MD, from the Memorial Sloan Kettering Cancer Center, discusses new data from a phase I study exploring the oral IDH2 inhibitor AG-221 in patients with advanced hematologic malignancies, primarily acute myelogenous leukemia and myelodysplastic syndrome.


Eytan Stein, MD

Articles

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

Dr. Stein on the SELECT-AML-1 Trial in Newly Diagnosed AML

Dr. Eytan Stein Discusses the IDH2 Inhibitor AG-221 in AML