Phase I/II Study of the All-Oral Combination of Revumenib (SNDX-5613) with Decitabine/Cedazuridine (ASTX727) and Venetoclax (SAVE) in R/R AML
Ghayas C. Issa, Branko Cuglievan, Naval Daver, Courtney D. DiNardo, Aziz Farhat, Nicholas J. Short, David McCall, Allison Pike, Sheila Tan, Brianna Kammerer, Aimee Marshal, Musa Yılmaz, Tapan M. Kadia, Naveen Pemmaraju, Maro Ohanian, Hussein A. Abbas, Abhishek Maiti, Alexandre Bazinet, Elias Jabbour, Koji Sasaki, Gautam Borthakur, Guillermo Montalban‐Bravo, Nitin Jain, Yesid Alvarado Valero, Farhad Ravandi, Guillermo Garcia‐Manero, Michael Andreeff, H. Kantarjian
Abstract
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.