The recent approval of the oral menin inhibitor revumenib brought much-needed treatment to patients with a challenging subset of disease: adults and children with relapsed or refractory acute leukemia harboring a lysine methyltransferase 2A gene (KMT2A) translocation or rearrangement. Approval was based on the phase II AUGMENT-101 study.¹ Updated findings from that trial,² along with a new study of revumenib in an all-oral triplet regimen,³ appear to bolster support for this novel agent, as investigators reported at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition.

Acute leukemia with a KMT2A rearrangement (KMT2Ar) accounts for about 10% of acute leukemias and is difficult to treat. Many patients relapse after chemotherapy and transplant, and salvage therapy is not often successful. In up to 40% of patients with acute myeloid leukemia (AML), leukemogenesis is driven by either KMT2A rearrangements or NPM1 mutations, critical genes that sit upstream from major targets in AML. Targeting this complex, therefore, is a rational approach in this challenging cancer, the speakers emphasized.

AUGMENT-101 Updated Analysis

Revumenib is an oral, small-molecule menin inhibitor that disrupts menin-KMT2A interactions. It was evaluated in AUGMENT-101, a trial of 116 adult and pediatric patients (median age, 37) with relapsed or refractory AML, acute lymphoblastic leukemia, or mixed-phenotype acute leukemia with KMT2A rearrangements or NPM1 mutations.

Updated findings for the KMT2A rearrangements cohort were reported by Ibrahim Aldoss, MD, Associate Professor, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.² (The NPM1 mutations cohort will be reported at a later date.) The main efficacy outcomes were complete remission plus complete remission with partial hematologic recovery, duration of complete remission plus complete remission with partial hematologic recovery, and conversion from transfusion dependence to independence.

Ibrahim Aldoss, MD

“AUGMENT-101 represents the largest evaluation of a targeted therapy for patients with relapsed or refractory KMT2Ar acute leukemias to date, including the largest pediatric menin inhibitor cohort,” said Dr. Aldoss. “In this updated phase II analysis, revumenib continued to consistently provide clinically meaningful responses in heavily pretreated patients, including high rates of measurable residual disease [MRD] negativity and ability to proceed to transplant.”

At a median follow-up of 6.1 months in the efficacy population of 97 patients (updated from 57 in the previous analysis), the overall response rate was 64%, with 23% of patients in complete remission or complete remission with partial hematologic recovery. “Responses were seen across different subgroups regardless of phenotype, regardless of prior transplant, prior lines of therapy, or prior venetoclax, and across different KMT2A translocations,” Dr. Aldoss reported.

Among the 18 patients achieving complete remission plus complete remission with partial hematologic recovery or composite complete remission who were MRD-evaluable, 61% and 58%, respectively, achieved MRD negativity. The updated median duration of complete remission plus complete remission with partial hematologic recovery response for the original 13 patients reported this past year was 13 months, with a long follow-up. Eight patients remain in follow-up without relapse or death.

Treatment-related adverse events led to dose reductions in 9% and treatment discontinuation in 5%. No patients stopped treatment because of cytopenias, differentiation syndrome, or QTc prolongation, the adverse effects of special interest, he said.

Oral Revumenib in Combination

The phase I/II SAVE study is evaluating whether combining revumenib with other active agents into an all-oral regimen could further improve outcomes. Treatment with revumenib plus oral decitabine/cedazuridine and venetoclax led to high remission rates in 33 patients with relapsed or refractory AML, with benefit seen across all studied biological subgroups, namely KMT2A rearrangements, NPM1 mutations, and NUP98 rearrangements,³ said Ghayas C. Issa, MD, Assistant Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center.

Revumenib at 113 mg or 163 mg was given orally every 12 hours. Decitabine/cedazuridine was administered at 35 mg/100 mg orally on days 1 to 5, and venetoclax at 400 mg was given orally on days 1 through 14. Patients received revumenib monotherapy after stem cell transplant for 1 year of maintenance.

Response to this combination was robust: 82% overall, 88% in patients with KMT2A rearrangements, 67% in those with NPM1 mutations, and 100% in patients with NUP98 rearrangements. Among the full population, 48% achieved complete remission or complete remission with partial hematologic recovery, and 39% achieved complete remission, with responses seen across genetic variants. Among responders, MRD negativity was achieved by 65% of patients, including 88% of patients with complete remission or complete remission with partial hematologic recovery, Dr. Issa reported.

At a median follow-up of 9 months, the 6-month duration of complete remission was 74%, and the median duration of response was not reached; the 6-month overall survival rate was 68%, with the median not reached. Ongoing responses are being seen with and without transplant.

Of note, 9% of patients experienced grade ≥ 3 QTc prolongation, and 3% of patients had grade ≥ 3 differentiation syndrome. All such cases were considered “at least possibly” related to revumenib, Dr. Issa said. 

DISCLOSURE: Dr. Aldoss has received fees for roles as a consultant or advisor for Pfizer, Amgen, Takeda, Kite Pharma, Ascentage Pharma, Adaptive Biotechnologies, Autolus Therapeutics, Sobi, Jazz Pharmaceuticals, and Syndax Pharmaceuticals. Dr. Issa reported financial relationships with Novartis, NuProbe, Syndax Pharmaceuticals, AbbVie, Kura Oncology, Sanofi, AstraZeneca, and Sanofi.

REFERENCES

1. Aldoss I, Issa GC, Thirman M, et al: Revumenib monotherapy in patients with relapsed/refractory KMT2Ar acute leukemia: Topline efficacy and safety results from the pivotal AUGMENT-101 phase 2 study. 2023 ASH Annual Meeting & Exposition. Abstract LBA-5. Presented December 12, 2023.

2. Aldoss I, Issa GC, Blachly JS, et al: Updated results and longer follow-up from the AUGMENT-101 phase 2 study of revumenib in all patients with relapsed or refractory KMT2Ar acute leukemia. 2024 ASH Annual Meeting & Exposition. Abstract 211. Presented December 7, 2024.

3. Issa GC, Cuglievan B, Daver N, et al: Phase I/II study of the all-oral combination of revumenib (SNDX-5613) with decitabine/cedazuridine (ASTX727) and venetoclax (SAVE) in R/R AML. 2024 ASH Annual Meeting & Exposition. Abstract 216. Presented December 7, 2024.

EXPERT POINT OF VIEW 

Rory M. Shallis, MD, Assistant Professor (Internal Medicine) at Yale School of Medicine, shared his thoughts about the latest findings for revumenib in studies presented at the 2024 American Society of Hematology (ASH) Annual Meeting. “The advent of the menin inhibitors represents one of the biggest forward leaps in AML [acute myeloid leukemia] management in years. The recent approval of revumenib for relapsed or refractory KMT2A-rearranged AML is a more-than-welcome addition to our current slate of options,” he said, noting that this biological subset of AML is “stubborn,” as the rate of relapse is high, and many patients fail to respond to front-line therapies.

Rory M. Shallis, MD

“The approximately 25% rate of complete remission or complete remission with partial hematologic recovery and the approximately 65% rate of overall response—with a median duration of response of 6 months—are significant,” stated Dr. Shallis. “These data were derived from patients who by virtue of a significant proportion of prior failures of transplantation and/or venetoclax-based therapy have limited meaningful alternatives. The goal for many of these patients is to proceed to hopefully curative transplant, which was performed in one-third of the study population.”

In addition to the relative success of revumenib as a relapsed or refractory monotherapy, the drug is also being studied in combination in this setting, namely as a component of an all-oral triplet regimen with decitabine/cedazuridine and venetoclax. The rates and duration of responses across the studied biological subgroups “look very attractive” in indirect comparison to those observed in the AUGMENT-101 population, Dr. Shallis pointed out. He noted that the SAVE population similarly had a heavy proportion of patients with prior venetoclax exposure. “But the relative safety of this triplet might someday lead to it being preferred in venetoclax-naive patients.” 

DISCLOSURE: Dr. Shallis has received fees for serving as a consultant or advisor to Syndax Pharmaceuticals and Kura Oncology.