Phase I/II Study of the All-Oral Combination of Revumenib (SNDX-5613) with Decitabine/Cedazuridine (ASTX727) and Venetoclax (SAVE) in R/R AML

Background: The menin inhibitor revumenib (previously SNDX-5613), is a potent, oral, selective inhibitor of the menin-KMT2A interaction which is a dependency in acute leukemia caused by either rearrangement of the KMT2A (KMT2Ar) or Nucleoporin 98 (NUP98r) genes, or mutation of the Nucleophosmin 1 gene (NPM1mt). KMT2Ar or NPM1mt leukemias are highly susceptible to induction of apoptosis through BCL2 inhibition, and dual Bcl-2 and menin inhibition led to synergistic activity in KMT2Ar or NPM1mt leukemia models (Carter BZ, Blood 2021; Fiskus W, BCJ 2022). Therefore, we designed a phase I/II, investigator-initiated trial of the all-oral combination of revumenib, venetoclax and the hypomethylating agent ASTX727 in children and adults with relapsed/refractory (R/R) acute myeloid leukemia (AML) (NCT05360160).

Methods: Patients (pts) with R/R AML or myeloid mixed-lineage acute leukemia (MPAL) aged 12 years and older were eligible. Dose escalation followed a 3+3 design. ASTX727 (decitabine/ cedazuridine) was administered at 35 mg/100 mg PO daily days 1-5, venetoclax at 400 mg (target dose) PO daily days 1-14, and revumenib 113 mg PO Q12h (dose level [DL] 0) or 163 mg PO Q12h (DL 1, used in phase II monotherapy), days 1-28 with either posaconazole or voriconazole (strong CYP3A4 inhibitors). Revumenib monotherapy following hematopoietic stem cell transplant (HSCT) was resumed for 1-year maintenance. An amendment to the protocol recommended holding revumenib after day 21 if cycle 1 day 14 bone marrow (BM) showed blasts <5%. Measurable residual disease (MRD) was assessed using multicolor flow cytometry (sensitivity 10^-4).

Results: As of 7/22/2024, 26 pts were enrolled, 12 pts on the phase I (6 pts for each DL), and 14 pts on the phase II. The recommended phase 2 dose for revumenib in this combination was identified as 163 mg PO Q12h with strong CYP3A4 inhibitors. The median age was 35 years (range, 12-79 years), including 5 children (age <18 years). Eleven pts had KMT2Ar (42%), 10 had NPM1mt (38%), 5 had NUP98r (20%), and 4 (15%) had extramedullary disease (EMD). The median prior lines of therapy was 3 (range 1-5), 17 pts (65%) had prior venetoclax, 11 pts (42%) had prior HSCT, and 2 pts had prior menin inhibitor. The most common all-grade treatment-emergent adverse events (TEAEs) were QT prolongation (58%), AST/ALT elevation (54%), febrile neutropenia (46%), hyperphosphatemia (46%), nausea (42%). Most common (>20%) TEAEs grade≥ 3 were febrile neutropenia (46%) and lung infection (42%), while treatment-related AEs (any agent) grade≥ 3 were thrombocytopenia (12%), neutropenia (8%), QT prolongation (8%) and differentiation syndrome (DS) in 1 pt (4%) (grade 3). One other pt had grade 2 DS, and all DS resolved with steroids. There was no early mortality (60 days).

The overall response rate (CR+CRh+CRp+CRi+PR+MLFS) was 88% (23/26 pts). Among the 3 non-responders, 1 had prior menin inhibitor, and all had prior hypomethylating agent and venetoclax; two had large burden EMD with marked improvement and reduction of BM blasts <5% but residual activity on PET scan. The CR/CRh rate was 58% (15 pts), with a CR rate of 46% (12 pts), CRh of 12% (3 pts), CRp of 12% (3 pts), PR of 4% (1 pt), and MLFS of 15% (4 pts). The MRD-negative rate by flow cytometry among pts with CR/CRh was 93% (13/14 pts) and 74% among responders (17/23 pts). Notably, the MRD-negative rate was lowest in NUP98r pts at 20% (1/5 pts). Twelve pts received HSCT following this combination (46%), with 3 pts resuming maintenance revumenib post-HSCT.

With a median follow-up of 6.6 months, the 6-months relapse-free survival was 59% (95% CI: 26%-81%) and overall survival was 74% (95% CI: 39%-83%). The median duration of response in those with CR/CRh was not reached. Two pts have completed maintenance post-HSCT and remain in remission.

Conclusions: The all-oral combination SAVE results in high rates of remission in pts with R/R AML with KMT2Ar, NPM1mt or NUP98r. In addition to the R/R cohort, a frontline cohort is now enrolling pts.

Issa:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Merck: Research Funding; Celgene: Research Funding; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Astex: Research Funding; Syndax Pharmaceuticals, Inc.: 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; Kura Oncology: 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; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees. Cuglievan:Syndax Pharmaceuticals, Inc.: Other: travel, accommodations, Research Funding; LLS: Research Funding; Octapharma: Other: travel, accommodations, research; Kura Oncology: Research Funding. Daver:Gilead: Consultancy, Research Funding; Glycomimetics: Research Funding; Syndax: Consultancy; Agios: Consultancy; Trovagene: Research Funding; Arog: Consultancy; KITE: Research Funding; Servier: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Novartis: Consultancy; Astellas: Consultancy, Research Funding; Celgene: Consultancy; Shattuck Labs: Consultancy; FATE Therapeutics: Other: Consulting Fees, Research Funding; Hanmi: Research Funding; Jazz: Consultancy; Trillium: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Novimmune: Research Funding; Menarini Group: Consultancy. DiNardo:Schrodinger: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Cleave: Research Funding; Gilead: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; AstraZeneca: Honoraria; Astex: Research Funding; Immunogen: Honoraria; ImmuneOnc: Research Funding; Foghorn: Research Funding; Riegel: Honoraria; Notable Labs: Honoraria; Genetech: Honoraria; GenMab: Consultancy, Honoraria, Other: data safety board; Jazz: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Loxo: Research Funding; Rigel: Research Funding; Astellas: Consultancy, Honoraria; Amgen: Consultancy; Stemline: Consultancy. Short:Amgen: Honoraria; Adaptive Biotechnologies: Honoraria; NextCure: Research Funding; Sanofi: Honoraria; Autolus: Honoraria; GSK: Consultancy, Research Funding; Astellas Pharma, Inc.: Honoraria, Research Funding; Stemline Therapeutics: Research Funding; Pfizer Inc.: Honoraria; BeiGene: Honoraria; Xencor: Research Funding; Novartis: Honoraria; Takeda Oncology: Honoraria, Research Funding. Yilmaz:daiichi sankyo: Honoraria, Research Funding. Kadia:Rigel: Honoraria; Regeneron: Research Funding; AstraZeneca: Research Funding; JAZZ: Research Funding; Abbvie: Consultancy, Research Funding; Amgen: Research Funding; Genentech: Consultancy, Research Funding; Ascentage: Research Funding; ASTEX: Research Funding; Sellas: Consultancy, Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Servier: Consultancy; Cellenkos: Research Funding; Novartis: Honoraria; BMS: Consultancy, Research Funding; DrenBio: Consultancy, Research Funding. Pemmaraju:Incyte: Honoraria; Roche Molecular Diagnostics: Honoraria; Stemline Therapeutics: Honoraria, Other: Travel Expenses, Research Funding; Springer Science + Business Media: Honoraria; Mustang Bio: Honoraria, Other: Travel Expenses, Research Funding; Aptitude Health: Honoraria; Celgene: Honoraria, Other: Travel Expenses; LFB Biotechnologies: Honoraria; Protagonist Therapeutics: Consultancy; ClearView Healthcare Partners: Consultancy; Bristol-Myers Squibb: Consultancy; Neopharm: Honoraria; Immunogen: Consultancy; CTI BioPharma: Consultancy; Astellas: Consultancy; Novartis: Honoraria, Research Funding; DAVA Oncology: Honoraria, Other: Travel Expenses; Pacylex: Consultancy; CareDx: Honoraria; Blueprint Medicines: Consultancy, Honoraria; Daiichi Sankyo: Research Funding; Cellectis: Research Funding; Affymetrix/Thermo Fisher Scientific: Research Funding; Triptych Health Partners: Consultancy; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; AbbVie: Honoraria, Other: Travel Expenses, Research Funding; Blueprint Medicines OncLive PeerView Institute for Medical Education: Consultancy, Other: advisory board; ASH Committee on Communications ASCO Cancer.NET Editorial Board: Other: Leadership; Karger Publishers: Other: Licenses; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: uncompensated. Ohanian:Bio-Path Holdings, Inc.: Consultancy. Abbas:Genentech: Research Funding; Illumina: Honoraria, Other: Inkind Support, Research Funding; GlaxoSmithKline: Research Funding; Alamar Biosciences: Honoraria; Molecular Partners: Consultancy; Blueprint Medicines Corporation: Research Funding; Ascentage: Research Funding; Enzyme By Design: Research Funding. Maiti:Chimeric Therapeutics: Research Funding; Lin Biosciences: Research Funding; Hibercell Inc.: Research Funding; CytoMed Therapeutics: Research Funding; Indapta Therapeutics: Research Funding; Inspirna: Research Funding. Jabbour:AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Sasaki:Otsuka: Other: Lecture fees; Enliven: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Daiichi-Sankyo: Consultancy; Chugai: Other: Lecture fees. Borthakur:Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Montalban-Bravo:Takeda: Research Funding; Rigel: Research Funding. Jain:Incyte: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Medisix: Research Funding; Ipsen: Consultancy, Honoraria, Other: Travel Support; Loxo Oncology: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel Support; NovalGen: Research Funding; Dialectic Therapeutics: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; MingSight: Honoraria, Research Funding; Servier: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support, Research Funding; TransThera Sciences: Research Funding; MEI Pharma: Consultancy, Honoraria, Other: Travel Support; Genentech: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pfizer: Research Funding; Newave: Research Funding; ADC Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel Support, Research Funding; Aprea Therapeutics: Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel Support, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel Support; CareDx: Consultancy, Honoraria, Other: Travel Support; BeiGene: Consultancy, Honoraria, Other: Travel Support; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding. Ravandi:Prelude: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Xencor: Research Funding; Astyex/Taiho: Research Funding; Astellas: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Garcia-Manero:Janssen: Research Funding; Merck: Research Funding; Genentech: Other: Personal fees; AbbVie: Research Funding; Curis: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Genentech: Research Funding; Astex: Research Funding; Helsinn: Other: Personal fees; Helsinn: Research Funding; Astex: Other: Personal fees; Onconova: Research Funding; Aprea: Research Funding; H3 Biomedicine: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Amphivena: Research Funding. Andreeff:Daiichi-Sankyo: Research Funding; Syndax: Honoraria, Research Funding; Aptose: Honoraria; Kintor Pharmaceutical: Research Funding; Paraza: Honoraria; Glycomimetics: Honoraria; Ona: Honoraria; Sellas: Honoraria, Research Funding; Oxford Biomedical: Research Funding; Roivant: Honoraria; Eterna: Current holder of stock options in a privately-held company, Honoraria, Research Funding; Ellipses: Research Funding; SentiBio: Current holder of stock options in a privately-held company, Honoraria, Research Funding; Oncolyze: Current holder of stock options in a privately-held company; Boehringer-Ingelheim: Honoraria; Chimerix: Current holder of stock options in a privately-held company. Kantarjian:AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria.