Background: Revumenib (SNDX-5613), a potent, selective small-molecule inhibitor of the menin-histone-lysine N-methyltransferase 2A (KMT2A) interaction, is being investigated in patients (pts) with relapsed/refractory (R/R) KMT2A-rearranged ( KMT2Ar) and nucleophosmin 1-mutated ( NPM1m) acute leukemias. An initial analysis of the phase 1 of AUGMENT-101 (NCT04065399) has been reported ( Nature. 2023;615:920-924). Here we report an update of >1 year additional experience in the phase 1 portion of the study, which has completed enrollment, with safety data from 131 treated pts and efficacy data in 80 pts with R/R KMT2Ar leukemia. Demographic data from pivotal phase 2 cohorts are included; safety and efficacy data of a preplannedanalysis will be reported at the meeting.

Methods: In phase 1, pts aged ≥30 days with R/R acute leukemias were assigned to 1 of 6 dose-escalation arms designed to identify a recommended phase 2 dose (RP2D) for concomitant administration of weak, moderate, or strong cytochrome P450 3A4 inhibitor (CYP3A4i) azole antifungal or no CYP3A4i. Pts received revumenib every 12 hours (q12h) or 3 times a day at a flat dose (≥40 kg) or a body surface area-based dose (<40 kg). Safety was assessed in all pts who received ≥1 dose of revumenib; responses are reported for all treated pts with KMT2Ar. In pts who underwent hematopoietic stem cell transplant (HSCT), responses reported are those achieved before HSCT.

The Phase 2 study was initiated following identification of an RP2D of 163 mg (95 mg/m 2 if <40 kg) q12h with a strong CYP3A4i in 28-day cycles until unacceptable toxicity, lack of at least morphological leukemia-free state (MLFS) by end of cycle 4, or progressive disease without clinical benefit as defined by the investigator. The phase 2 primary objectives are evaluation of safety and tolerability of revumenib and assessment of the complete remission (CR) + CR with partial hematologic recovery (CRh) rate. The safety and efficacy of revumenib at an RP2D is being explored in 3 expansion cohorts: Cohort 2A, KMT2Ar acute lymphoblastic leukemia (ALL)/mixed phenotype acute leukemia; Cohort 2B, KMT2Ar acute myeloid leukemia (AML); and Cohort 2C, NPM1m AML. A preplanned pooled analysis of adult and pediatric pts with KMT2Ar acute leukemia will be conducted when a subset of Cohorts 2A+2B pts have completed a minimum of 4 cycles or have discontinued therapy.

Results: Phase 1: As of June 19, 2023, 80 pts with R/R KMT2Ar acute leukemia were treated with revumenib in the 6 dose-escalation arms (Table 1). In adults with AML (n=51), the largest KMT2Ar subgroup, CR+CRh was 28% and overall response rate (ORR) was 59%. Responses were consistent in ALL/other leukemia subtype (n=15), with 27% CR+CRh and 53% ORR. ORR (61%) was similar in pediatric pts (<18 years, n=18), with 22% proceeding to HSCT. Although similar percentages of adult and children proceeded to transplant, consistent with common clinical practice in pediatrics, 75% of children transplanted went on to HSCT prior to achieving a CR/CRh (2 MLFS, 1 CRp) versus 17% of adults. In the safety population (n=131), 24% of pts had a ≥Grade 3 treatment-related adverse event (TRAE), with Grade 3 QTc prolongation in 8% and differentiation syndrome in 2% (Table 1). QTc prolongation remained as the only dose-limiting toxicity; no patients experienced ventricular arrhythmias. In addition, based on updated phase 1 pharmacokinetics, clinical activity, and safety data, an RP2D of 276 mg q12h without a strong CYP3A4i was established.

Phase 2: In a preliminary analysis of Cohorts 2A and 2B (June 19, 2023), 88 pts with KMT2Ar acute leukemia were enrolled and treated with revumenib at an RP2D (Table 2). Ages ranged from 1.3 to 75 years (22 aged <18 y; Table 2). Leukemia subtypes included ALL (15%), AML (81%), and other (3%). Pts were heavily pretreated, having received a median of 3 prior lines of therapy (range 1-12); 38% received ≥4 prior lines and 48% had prior HSCT.

Conclusions: These phase 1 data continue to demonstrate deep responses to revumenib and a manageable safety profile in heavily pretreated patients with R/R KMT2Ar acute leukemia across ages and subtypes. The lack of targeted therapies approved for KMT2Ar leukemia indicate the need for further investigation of novel, potentially transformative therapies such as revumenib. Enrollment in the AUGMENT-101 trial is ongoing. Pivotal Phase 2 safety and efficacy data for the KMT2Ar population will be reported at the meeting.

Aldoss:Takeda: Consultancy; Jazz: Consultancy; Sobi: Consultancy; KiTE: Consultancy; Amgen: Consultancy, Honoraria; Pfizer: Consultancy. Issa:Celgene: Research Funding; Kura Oncology: Consultancy, Research Funding; Syndax: Research Funding; Novartis: Consultancy, Research Funding; NuProbe: Consultancy; Merck: Research Funding. Thirman:Syndax: Research Funding; Nurix: Research Funding; AbbVie: Research Funding; Merck: Research Funding; AbbVie: Honoraria. DiPersio:Bioline: Consultancy; Magenta: Current holder of stock options in a privately-held company, Other: Ownership Investment, Patents & Royalties; Rivervest: Consultancy; Vertex: Consultancy; WUGEN: Current holder of stock options in a privately-held company, Other: Ownership Investment, Patents & Royalties, Research Funding; Macrogenics: Research Funding. Blachly:AstraZeneca: Consultancy; AbbVie: Consultancy; Leukemia Diagnostic Device: Patents & Royalties: Being prosecuted; Epigenetic classification of leukemia: Patents & Royalties: PCT conversion filed; Astellas: Consultancy. Mannis:Abbvie: Consultancy; Agios: Consultancy; Macrogenics: Honoraria; Astellas: Consultancy; BMS/Celgene: Consultancy; Genentech: Consultancy; Stemline: Consultancy. Perl:BMS: Honoraria; BerGen Bio: Honoraria; Beat AML: Other: Participation on a Data Safety Monitoring Board or Advisory Board; Forma: Consultancy; Foghorn: Consultancy; Immunogen: Honoraria; Genentech: Honoraria; Syndax: Research Funding; FujiFilm: Research Funding; Bayer: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptose: Honoraria; Rigel: Honoraria; Actinium: Honoraria. Dickens:American Society of Pediatric Hematology Oncology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Tempus Inc.: Honoraria; American Academy of Pediatrics: Membership on an entity's Board of Directors or advisory committees; Iowa Cancer Consortium: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding. McMahon:Syndax Pharmaceuticals: Research Funding; Syros Pharmaceuticals: Research Funding; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Arcellx: Membership on an entity's Board of Directors or advisory committees. Traer:Incyte: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Schrodinger: Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees. Zwaan:ITCC Hem Malignancies Committee: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceutical: Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Research Funding; Takeda: Research Funding; Sanofi: Other: Advisory role; BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy, Other: Advisory role; Kura Oncology: Consultancy; Abbvie: Research Funding; Syndax: Research Funding; Gilead: Consultancy. Grove:Otsuka Australia: Consultancy; Astellas: Consultancy, Honoraria; Abbvie: Consultancy. Stone:Abbvie: Consultancy. Shami:Daiichi Sankyo: Other: Participation in Data Safety Monitoring/Advisory Board; Syndax Pharmaceuticals: Research Funding; Chimerix: Research Funding; Gilead: Other: Participation in Data Safety Monitoring/Advisory Board; BMS: Other: Participation in Data Safety Monitoring/Advisory Board; JSK Therapeutics: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Abcuro: Research Funding; RJH Biosciences: Other: Participation in Data Safety Monitoring/Advisory Board; National Cancer Center Network: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Participation in Data Safety Monitoring/Advisory Board. Mantzaris:Kite, a Gilead company: Honoraria. Greenwood:Jazz: Honoraria; Amgen: Honoraria, Other: Drug supply for a trial; Servier: Honoraria, Other: Assay costs, shipping costs - trial related. Shukla:Syndax Pharmaceuticals: Honoraria. Gu:Syndax Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Bagley:Syndax Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Madigan:Syndax Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Nguyen:Syndax Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. McNeer:Syndax Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company; Astrazeneca: Research Funding. Stein:Syros: Consultancy; Aptose: Consultancy; Daiichi: Consultancy; Calithera: Consultancy; Servier: Consultancy; Foghorn: Consultancy; CTI Biopharma: Consultancy; OnCusp: Consultancy; Syndax: Consultancy; Gilead: Consultancy; Neoleukin: Consultancy; Abbvie: Consultancy; Genesis: Consultancy; Genentech: Consultancy; Menarini: Consultancy; Jazz: Consultancy; Agios: Consultancy; Janssen: Consultancy; PinotBio: Consultancy; Novartis: Consultancy; Bristol Myers Squib: Consultancy, Research Funding; Eisai: Research Funding; Astellas: Consultancy; Ono Pharma: Consultancy; Blueprint: Consultancy.

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