denotes an abstract that is clinically relevant.
denotes that this is a recommended PHD Trainee Session.
denotes that this is a ticketed session.Session: 616. Acute Myeloid Leukemias: Investigational Drug and Cellular Therapies: Poster II
Hematology Disease Topics & Pathways:
Adult, Acute Myeloid Malignancies, Research, Clinical trials, Combination therapy, AML, Drug development, Clinical Research, Chemotherapy, Diseases, Treatment Considerations, Adverse Events, Non-Biological therapies, Myeloid Malignancies, Study Population, Human
Background: In approximately 35–40% of acute myeloid leukemia (AML) cases, leukemogenesis is driven by nucleophosmin 1 (NPM1) mutations or rearrangements in lysine methyltransferase 2A (KMT2A). Ziftomenib, a potent selective menin inhibitor, has shown clinical activity as monotherapy in adult relapsed/refractory (R/R) NPM1-mutated (NPM1-m) or KMT2A-rearranged (KMT2A-r) AML. KOMET‑007, an ongoing, open-label, dose escalation (phase 1a) and expansion (phase 1b) study, aims to evaluate ziftomenib in combination with standard chemotherapies in adults with newly diagnosed and R/R NPM1-m or KMT2A-r AML (NCT05735184). Here we report interim results from phase 1a in patients with R/R AML.
Methods: Adults (age ≥18 years) with R/R NPM1-m or KMT2A-r AML were enrolled into separate dose escalation cohorts for each genotype. Following a rule-based approach, at least six dose-limiting toxicity (DLT)-evaluable patients were assigned to each cohort where ziftomenib (200, 400, or 600 mg, once daily) was escalated with standard doses of venetoclax and azacitidine (Ven/Aza). Ziftomenib was administered orally from Cycle 1 Day 8 and continuously thereafter. Primary endpoints in phase 1a were DLTs and adverse events (AEs); key secondary endpoints included composite complete remission rates (CRc; defined as complete remission [CR] or CR with partial or incomplete hematological recovery). Here we present data for the first 34 patients (pts) treated in the R/R cohorts (ziftomenib 200 mg, n=18; 400 mg, n=16). Enrollment in the 600 mg cohort is ongoing.
Results: As of the June 21, 2024 data cutoff, median age was 56 (range 23–86) years, and 50% were female; 41% (14/34) had NPM1-m and 59% (20/34) had KMT2A-r. Median follow-up was 35 and 14 weeks at 200 mg and 400 mg, respectively, for R/R pts with NPM1-m; and 15 and 14 weeks for those with KMT2A-r. Median number of prior therapies was 2 (range 1–8); 32% (11/34) had prior transplant; and 74% (25/34) were menin inhibitor-naive, including 68% (17/25) who had prior Ven exposure. No DLTs or ziftomenib-induced QTc prolongation were reported. The most common (≥20% of patients) grade (Gr) ≥3 treatment-emergent AEs (TEAEs) were febrile neutropenia (35%), decreased platelet count (35%), anemia (26%), decreased neutrophil count (24%), and pneumonia (24%). Gr≥3 ziftomenib- and/or backbone-related AEs occurred in 44% of patients, including decreased platelet count (18%), decreased neutrophil count (15%), and anemia (12%). On-target differentiation syndrome (DS) occurred in 12% (4/34) of R/R patients (1 NPM1-m [400 mg, Gr3] and 3 KMT2A-r [200 mg, 1-Gr3; 400 mg, 1-Gr2 and 1-Gr3]), and all cases were manageable per the DS guidance.
Twenty-four menin inhibitor-naive patients (NPM1-m, n=11; KMT2A-r, n=13) had ≥1 response assessment as of the data cutoff. Among R/R NPM1-m patients, the overall response rate (ORR) was 100% (5/5) at 200 mg and 67% (4/6) at 400 mg; CRc rates were 80% (4/5) at 200 mg and 50% (3/6) at 400 mg. In NPM1-m patients who received prior Ven, ORR was 100% (3/3) at 200 mg and 50% (2/4) at 400 mg. For R/R KMT2A-r patients, ORR was 43% (3/7) at 200 mg and 33% (2/6) at 400 mg; CRc rates were 29% (2/7) at 200 mg and 17% (1/6) at 400 mg. In KMT2A-r patients who received prior Ven, ORR was 40% (2/5) at 200 mg and 25% (1/4) at 400 mg. The study is ongoing, with 50% (7/14) of R/R NPM1-m patients (200 mg, n=4; 400 mg, n=3) and 30% (6/20) of R/R KMT2A‑r patients (200 mg, n=3; 400 mg, n=3) remaining on study.
Conclusion: In the ongoing KOMET-007 study, ziftomenib combined with Ven/Aza was well tolerated at the dose levels tested to date and continued to demonstrate promising clinical activity in R/R pts. No DLTs or ziftomenib-induced QTc prolongation were reported. On-target DS occurred in 12%, including in 3 of 20 KMT2A-r patients, and all patients had resolution of DS with appropriate management. In response-evaluable, menin inhibitor-naive R/R patients, CRc rates were 80% at 200 mg and 50% at 400 mg for NPM1-m AML; and 29% and 17% for KMT2A-r AML, respectively. Clinical activity was also demonstrated in previously Ven-exposed NPM1-m and KMT2A-r patients. Based on these encouraging initial results, a dose expansion phase evaluating this triplet combination in newly diagnosed and R/R NPM1-m and KMT2A-r AML patients is underway. Updated results will be presented, as data from the 400 mg cohorts continue to mature and 600 mg cohorts are enrolling.
Disclosures: Fathi: Forma: Consultancy; PureTech: Consultancy; Orum: Consultancy; Menarini Group: Consultancy; AstraZeneca: Honoraria; Gilead: Consultancy; Remix: Consultancy; EnClear: Consultancy; Astellas: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Ispen: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Rigel: Consultancy; Autolus: Consultancy; Foghorn, Blueprint Medicines, Kura, Trillium: Honoraria; Kite: Consultancy; Mablytics: Consultancy; MorphoSys: Consultancy; ImmunoGen: Consultancy; BMS/Celgene: Consultancy; Agios: Ended employment in the past 24 months; AbbVie, BMS/Celgene, and Agios/Servier: Research Funding; Ipsen: Consultancy; Genentech: Honoraria; Novartis: Consultancy; Servier: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding. Issa: Kura Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Merck: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Syndax Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Astex: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Celgene: Research Funding. Wang: UptoDate: Other: Section Editor; Dava Oncology: Speakers Bureau; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rigel: Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sellas: Membership on an entity's Board of Directors or advisory committees; Stemline: Membership on an entity's Board of Directors or advisory committees; Sumitomo Pharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Kura: Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Schrodinger: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Immunogen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mana: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Award Committee, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding, Speakers Bureau. Erba: Stemline: Consultancy, Other: Advisory Board/Consultant; Servier: Consultancy, Other: Advisory Board/Consultant, Research Funding, Speakers Bureau; Schrodinger: Consultancy, Other: Advisory Board/Consultant; Pfizer: Consultancy, Other: Advisory Board/Consultant; Novartis: Consultancy, Other: Advisory Board/Consultant, Research Funding, Speakers Bureau; Macrogenics: Consultancy, Other: Advisory Board/Consultant, Research Funding; Kura Oncology: Consultancy, Other: Advisory Board/Consultant, Research Funding; Jazz: Consultancy, Other: Advisory Board/Consultant, Speakers Bureau; Incyte: Consultancy, Other: Advisory Board/Consultant; Immunogen: Consultancy, Other: Advisory Board/Consultant; Glycomimetics: Consultancy, Other: Advisory Board; Steering Committee member, Research Funding; Genentech: Consultancy, Other: Advisory Board; Daiichi Sankyo: Consultancy, Other, Research Funding; Celgene: Consultancy, Other: Advisory Board; Chair, Myeloid Neoplasms Repository Study., Research Funding, Speakers Bureau; BMS: Consultancy, Other: Advisory Board; Chair, Myeloid Neoplasms Repository Study., Speakers Bureau; Astellas: Consultancy, Other: Advisory Board; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Chair, Independent Review Committee for VIALE A and VIALE C, Research Funding; Sumitomo Pharma: Consultancy, Other: Advisory Board/Consultant, Research Funding; Syros: Consultancy, Other: Advisory Board/Consultant; Takeda: Consultancy, Other: Advisory Board/Consultant; Trillium: Consultancy, Other: Advisory Board/Consultant; ALX Oncology: Research Funding; Aptose: Research Funding; Ascentage: Research Funding; Oryzon: Research Funding; PTE: Research Funding; Taiho Oncology: Research Funding. Altman: Astellas: Honoraria, Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board; MD Educations: Other: advisory board and education; Rigel: Other: advisory board; Aptitude Health: Other: advisor; Gilead: Other: advisory board; Curio: Other: advisory board; Dark Blue Therapeutics: Other: advisory board; Treadwell Therapeutics: Other: advisory board; VJ HemOnc: Other: advisory board and education. Balasubramanian: Alexion AstraZeneca: Speakers Bureau; Kura Oncology: Research Funding. Roboz: Novartis, Pfizer, Roche, GlaxoSmithKline, BMS, Syndax, Rigel: Consultancy; Janssen: Research Funding; OncoPrecision: Current holder of stock options in a privately-held company, Honoraria; AbbVie, Amgen, Astrazeneca, Caribou Biosciences, Celgene, Daiichi Sankyo, Ellipses pharma, Geron, GSK, Glycomimetics, Janssen, Jasper Pharmaceuticals, Jazz Pharmaceuticals, Molecular Partners, Oncoverity: Consultancy. McMahon: Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals, Inc.: Research Funding; Syros Pharmaceuticals: Research Funding. Palmisiano: BMS: Consultancy; Abbvie: Consultancy, Research Funding; Rigel: Consultancy. Madanat: Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology, SOBI, Rigel Pharmaceuticals, Geron, Cogent Biosciences, and Novartis: Other: Advisory Board; Blueprint Medicines, MD Education and Morphosys: Other: Supporting or attending meetings and/or travel; BMS, Kura Oncology, Blueprint Medicines, Geron: Consultancy. Pratz: Kura Oncology: Research Funding; Immunogen: Consultancy; AbbVie: Consultancy, Research Funding. Yaghmour: Astellas: Speakers Bureau; Secura Bio: Speakers Bureau; Incyte: Speakers Bureau; SOBI: Speakers Bureau; Kite: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Jazz: Speakers Bureau; Servier: Speakers Bureau; Rigel: Speakers Bureau; GSK: Speakers Bureau; Astazeneca: Other: Advisory Board; Daiichi: Other: Advisory Board; Abbvie: Other: Advisory Board; Pharmacyclics: Research Funding; USC Keck School of Medicine: Current Employment; Stemline therapeutic: Speakers Bureau; ABBVie: Speakers Bureau; Blueprint: Speakers Bureau; Alexion: Other: consult. Wei: Zai Lab: Ended employment in the past 24 months; Orca Bio: Consultancy; Kura Oncology, Inc: Consultancy. Riches: Kura Oncology, Inc: Current Employment, Current equity holder in publicly-traded company. Corum: Kura Oncology, Inc: Current Employment, Current equity holder in publicly-traded company. Leoni: Kura Oncology, Inc: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Dale: Kura Oncology, Inc: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Zeidan: Karyopharm: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Regeneron: Consultancy, Honoraria; Schroedinger: Consultancy, Honoraria; Treadwell: Consultancy, Honoraria; Faron: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Hikma: Consultancy, Honoraria; Glycomimetics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Geron: Consultancy, Honoraria, Research Funding; Zentalis: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Keros: Consultancy, Honoraria; Kura: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Consultancy, Honoraria; Lava Therapeutics: Consultancy, Honoraria; Medus: Consultancy, Honoraria; Notable: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Rigel: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Sumitomo: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Vinerx: Consultancy, Honoraria; Astex: Research Funding; Shattuck Labs: Research Funding; Chiesi: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Research Funding; BioCryst: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; ALX Oncology: Consultancy, Honoraria; Akeso Pharma: Consultancy, Honoraria; Agios: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding.