Naval Daver, MD on Phase 1/2 Trial of DSP-5336 in R/R Acute Leukemia

CancerNetwork® spoke with Naval G. Daver, MD, professor and director of the Leukemia Research Alliance Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, about the clinical implications for the use of DSP-5336 in relapsed/refractory acute leukemia based on findings from a first-in-human phase 1/2 trial (NCT04988555). Investigators of this trial assessed the clinical activity of the menin inhibitor and aimed to determine a recommended phase 2 dose.

Daver highlighted potential development for a larger single-agent phase 2 study assessing the use of DSP-5336 in patients with relapsed/refractory acute leukemia. Although he did not identify a specific target population, he identified a list of menin-sensitive biomarkers that may be included in the next phase such as NPM1 and NUP98.

Among patients with no prior treatment with menin inhibitors and KMT2A rearrangements or NPM1 mutations treated at greater than 140 mg of DSP-5336 twice daily (n = 22), the objective response rate (ORR) was 45%, and the complete response (CR) plus CR with hematologic recovery (CR+CRh) rate was 23%. Across all dose levels (40 mg to 300 mg twice daily) in patients with no prior treatment with menin inhibitors with KMT2A rearrangements or NPM1 mutations, ORR and CR+CRh rate was 32% and 16%, respectively.

Daver presented these findings at the 2024 European Hematology Association (EHA) Congress.

Transcript:

At this time, from a regulatory point and getting these drugs available to patients outside of large academic centers currently running the trials like ours, we're looking at the potential for developing a larger phase 2 single-agent DSP-5336 In relapsed/refractory acute myeloid leukemia [AML]. We haven't decided exactly the target population, but it's probably going to be a mix of different aberrations that are known to upregulate MEIS1 and HOXA9, which are the key biomarkers for menin sensitivity; probably NPM1, KMT2A, NUP98, UBTF, and a few others. That's probably the initial direction: to see if we could produce and reproduce the good CR+CRh [and] overall response rate, while maintaining the very encouraging safety in terms of both differentiation and cardiac issues and see if there's a path to approval in the near future.

[Thinking] more in the long term, [we’re] going to be using combination approaches. We're already looking at starting to develop combinations, both with azacitidine/venetoclax [Venclexta] with DSP-5336. Given the rise of venetoclax as a standard frontline therapy for AML, the question is, “can you add DSP-5336 in patients who have target aberrations like MLL, KMT2A rearrangements, or NPM1, and further improve their response rate, response depth outcome, in combination with FLT3 inhibitors?” We're going to see some of these combinations start hopefully in the next month or 2, and then see if these further boost the response rate, depth of response, durability, and outcome. Personally, I feel that, in the end, the menin inhibitors will have their best use in combinations, ideally, in the frontline setting, where we're going to see not just good response rates and CR+CRh, but actually convert the cure rates from 30% to 35% with HMA-VEN [hypomethylating agents plus venetoclax] at 3 years to potentially up to 50% to 60%. That is really where we want to develop these [combination therapies] in the future.

Reference

Naver D, Erba H, Watts JM, et al. First-in-human phase 1/2 study of the menin-MLL inhibitor DSP-5336 in patients with relapsed or refractory acute leukemia: updated results from dose escalation. Presented at: European Hematologic Association 2024 Hybrid Congress; June 13-16, 2024; Madrid, Spain. Abstract S132.