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.