Phase 1 study of revumenib in combination with intensive chemotherapy (IC) in patients (Pts) with newly diagnosed (ND) Acute Myeloid Leukemia (AML) harboring genetic alterations in KMT2A, NPM1, or NUP98: SNDX-5613-0708

Abstract Introduction Acute leukemias (AL) harboring a KMT2A or NUP98 rearrangement (KMT2Ar or NUP98r) confer unfavorable prognosis, and while an NPM1 mutation (NPM1m) is generally considered favorable risk, ~50% of adults will relapse. The menin-KMT2A interaction leads to leukemogenesis and is central to AL harboring KMT2Ar, NPM1m, or NUP98r; disruption of this interaction may restore differentiation. Revumenib, a first-in-class, oral, potent, and selective menin inhibitor, has shown antileukemic activity as monotherapy in relapsed/refractory KMT2Ar AL and NPM1m AML in the phase 1/2 AUGMENT-101 study (NCT04065399) and in combination with standard of care in ND KMT2Ar or NPM1m AML pts unfit for IC in the phase 1/2 BEAT-AML study (NCT03013998). Data from AUGMENT-101 also showed clinical responses with revumenib in a small cohort of pts with NUP98r AML. Early efficacy of revumenib in ND AML supports further exploration in combination with IC. Here we report results from the dose-level (DL) 1 cohort of the dose-escalation portion of a phase 1 study of revumenib in combination with IC in pts with ND AML harboring a KMT2Ar, NPM1m, or NUP98r. Methods SNDX-5613-0708 is a global, phase 1, multicenter, open-label, dose-escalation and dose-expansion study of revumenib in combination with IC (NCT06226571). Eligible pts are 18-75yrs of age with ND KMT2Ar, NPM1m, or NUP98r AML, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (0-1 if >65yrs) and candidates for IC. In the dose-escalation phase, pts receive induction with revumenib and IC (cytarabine and daunorubicin or idarubicin) for up to two 28-day cycles. In DL1, revumenib is given twice daily at 110mg or 220mg with/without a strong CYP3A4 inhibitor, respectively; in DL2, pts receive revumenib twice daily at 160mg or 270mg with/without a strong CYP3A4 inhibitor, respectively. Pts who achieve complete remission (CR) or CRi after induction receive consolidation with revumenib and high-dose cytarabine for up to four 28-day cycles. Pts who maintain CR or CRi after ≥3 cycles of consolidation receive revumenib maintenance until disease progression. Eligible pts who achieve remission can undergo hematopoietic stem cell transplant (HSCT) prior to maintenance therapy. Primary endpoints are occurrence of dose-limiting toxicities (DLTs) and frequency/severity of treatment-emergent adverse events (TEAEs), treatment-related AEs (TRAEs), and serious AEs (SAEs). Secondary endpoints are pharmacokinetic (PK) parameters. Exploratory endpoints are CR rate, composite CR rate (CRc; CR+CR with incomplete platelet recovery), objective response rate (ORR; CRc+morphologic leukemia-free state), time to response (TTR), and measurable residual disease (MRD)-negative CR rate (assessed locally). Results At data cutoff (6/3/25), 6 of 7 pts dosed at DL1 were DLT evaluable. Among the safety-evaluable population (n=7), median (range) age was 37yrs (27-56), 4 of 7 pts had ECOG performance status of 0-1, and all pts had KMT2Ar. One pt discontinued treatment during induction due to an AE. One DLT (QT prolongation) occurred; no deaths were observed. TEAEs of any grade occurred in 7 pts; most common were nausea and decreased neutrophils (n=5 each). Grade ≥3 TEAEs occurred in 7 pts; most common were decreases in neutrophils, platelets, and white blood cells (n=4 each). Most common TRAEs related to revumenib were decreased neutrophils (n=4) and nausea (n=3); most common grade ≥3 were decreased neutrophils (n=3), anemia, and decreased platelets (n=2 each). SAEs were viral gastroenteritis, pneumonia, staphylococcal sepsis, and febrile neutropenia (n=1 each). In the 7 pts enrolled in DL1, average revumenib concentration remained above the inhibitory concentration resulting in 90% inhibition (IC90) of the menin–KMT2A interaction throughout the dosing period. CR rate, CRc rate, and ORR were all 100% (7/7). Median (range) TTR was 0.69mo (0.6-0.8). All pts tested for MRD negativity achieved MRD-negative CR by local assessment (n=6). Four out of 7 pts proceeded to HSCT, at the time of the data cutoff. Conclusions The safety profile of revumenib in combination with IC was consistent with the known safety profile of revumenib. PK findings support exposure targets above the IC90. Early efficacy demonstrated deep responses with all tested pts achieving MRD-negative CR. Based on findings from revumenib DL1, SNDX-5613-0708 enrollment is ongoing; additional data inclusive of DL2 will be presented.

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