CancerNetwork® spoke with Naval G. Daver, MD, professor and director of the Leukemia Analysis Alliance Program within the Division of Leukemia at The College of Texas MD Anderson Most cancers Middle, concerning the medical implications for the usage of DSP-5336 in relapsed/refractory acute leukemia based mostly on findings from a first-in-human part 1/2 trial (NCT04988555). Investigators of this trial assessed the medical exercise of the menin inhibitor and aimed to find out a beneficial part 2 dose.
Daver highlighted potential growth for a bigger single-agent part 2 research assessing the usage of DSP-5336 in sufferers with relapsed/refractory acute leukemia. Though he didn’t determine a selected goal inhabitants, he recognized an inventory of menin-sensitive biomarkers that could be included within the subsequent part resembling NPM1 and NUP98.
Amongst sufferers with no prior remedy with menin inhibitors and KMT2A rearrangements or NPM1 mutations handled at better than 140 mg of DSP-5336 twice every day (n = 22), the target response charge (ORR) was 45%, and the whole response (CR) plus CR with hematologic restoration (CR+CRh) charge was 23%. Throughout all dose ranges (40 mg to 300 mg twice every day) in sufferers with no prior remedy with menin inhibitors with KMT2A rearrangements or NPM1 mutations, ORR and CR+CRh charge was 32% and 16%, respectively.
Daver introduced these findings on the 2024 European Hematology Affiliation (EHA) Congress.
Transcript:
Presently, from a regulatory level and getting these medicine out there to sufferers outdoors of enormous educational facilities presently working the trials like ours, we’re wanting on the potential for creating a bigger part 2 single-agent DSP-5336 In relapsed/refractory acute myeloid leukemia [AML]. We have not determined precisely the goal inhabitants, but it surely’s most likely going to be a mixture of totally different aberrations which can be identified to upregulate MEIS1 and HOXA9, that are the important thing biomarkers for menin sensitivity; most likely NPM1, KMT2A, NUP98, UBTF, and some others. That is most likely the preliminary path: to see if we might produce and reproduce the nice CR+CRh [and] total response charge, whereas sustaining the very encouraging security by way of each differentiation and cardiac points and see if there is a path to approval within the close to future.
[Thinking] extra in the long run, [we’re] going to be utilizing mixture approaches. We’re already beginning to develop combos, each with azacitidine/venetoclax [Venclexta] with DSP-5336. Given the rise of venetoclax as a normal frontline remedy for AML, the query is, “are you able to add DSP-5336 in sufferers who’ve goal aberrations like MLL, KMT2A rearrangements, or NPM1, and additional enhance their response charge, response depth consequence, together with FLT3 inhibitors?” We will see a few of these combos begin hopefully within the subsequent month or 2, after which see if these additional increase the response charge, depth of response, sturdiness, and consequence. Personally, I really feel that, in the long run, the menin inhibitors can have their greatest use in combos, ideally, within the frontline setting, the place we will see not simply good response charges and CR+CRh, however really convert the remedy charges from 30% to 35% with HMA-VEN [hypomethylating agents plus venetoclax] at 3 years to probably as much as 50% to 60%. That’s actually the place we wish to develop these [combination therapies] sooner or later.
Reference
Naver D, Erba H, Watts JM, et al. First-in-human part 1/2 research of the menin-MLL inhibitor DSP-5336 in sufferers with relapsed or refractory acute leukemia: up to date outcomes from dose escalation. Offered at: European Hematologic Affiliation 2024 Hybrid Congress; June 13-16, 2024; Madrid, Spain. Summary S132.
