On May 7, 2025 Syndax Pharmaceuticals (Nasdaq: SNDX), a commercial-stage biopharmaceutical company advancing innovative cancer therapies, reported that data from the pivotal Phase 2 portion of the AUGMENT-101 trial of revumenib, a first-in-class menin inhibitor, in patients with relapsed or refractory (R/R) mutant NPM1 (mNPM1) acute myeloid leukemia (AML) have been published in Blood (Press release, Syndax, MAY 7, 2025, View Source [SID1234652651]).
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"We are thrilled to publish the first positive pivotal dataset in patients with an NPM1 mutation, the most common genetic alteration observed in AML," said Neil Gallagher, M.D., Ph.D., President, Head of Research and Development at Syndax. "These important data support the safety and efficacy of revumenib in relapsed or refractory mNPM1 AML and serve as the foundation for the sNDA we submitted to the FDA under its RTOR program."
"These are impressive, landmark results which underscore the potential for revumenib to meaningfully advance the standard of care for patients with R/R mNPM1 AML, a difficult to treat disease with a poor prognosis," said Martha L. Arellano, M.D., Professor of Hematology and Oncology, Winship Cancer Institute of Emory University, and Principal Investigator in the AUGMENT-101 trial. "In the older, heavily pretreated population enrolled in this trial, it is very encouraging to observe that nearly 50% of patients achieved an overall response and that revumenib was generally well-tolerated. These findings add to the growing body of evidence supporting revumenib’s paradigm-changing potential as treatment for a significant subset of acute leukemias."
In November 2024, revumenib was FDA approved as Revuforj for the treatment of R/R acute leukemia with a KMT2A translocation in adult and pediatric patients one year and older. In April 2025, Syndax completed the submission of a supplemental New Drug Application (sNDA) for revumenib in R/R mNPM1 AML under the FDA’s Real-Time Oncology Review (RTOR) program. The sNDA is supported by the positive pivotal data reported from the Phase 2 portion of the AUGMENT-101 trial.
About the published data
The publication entitled "Menin inhibition with revumenib for NPM1-mutated (NPM1m) relapsed or refractory acute myeloid leukemia: AUGMENT-101" reports results from patients with R/R mNPM1 AML who received revumenib in the pivotal Phase 2 portion of the AUGMENT-101 trial.
The protocol-defined efficacy-evaluable population for the primary analysis included the first 64 adult patients with R/R mNPM1 AML. In this efficacy population, the median age was 65 (range: 19, 84). Patients were heavily pretreated with 36% having received three or more prior lines of therapy and 22% having received four or more prior lines of therapy (median prior lines: 2). 75% of patients were previously treated with venetoclax.
The study met the primary efficacy endpoint with a complete remission (CR) plus CR with partial hematological recovery (CRh) rate of 23% (15/64; 95% confidence interval [CI]: 14%-36%; one-sided p-value =0.0014). The median time to first CR+CRh was 2.76 months (range: 1.8-8.8) and the median duration of CR+CRh was 4.7 months (95% CI: 1.2-8.2). Responses were observed across the various subgroups assessed, including patients with multiple prior lines of therapy, prior venetoclax exposure, prior HSCT, and prior FLT3 inhibitor use.
The overall response rate (ORR)1 was 47% (30/64). Of the responders, 17% (5/30) proceeded to hematopoietic stem cell transplant (HSCT) while in remission, with three patients resuming revumenib after HSCT. The duration of therapy with revumenib post-transplant ranged from 2 to 60 weeks.
In this single-arm trial, the median overall survival (OS) observed was 4.0 months (95% CI: 2.5-7.2) among all 64 adults in the primary efficacy analysis based on the Kaplan-Meier estimate. The median OS observed was 23.3 months (95% CI: 7.2-not reached) among the 15 CR+CRh responders based on the Kaplan-Meier estimate.
The safety population included 84 adult and pediatric patients with R/R mNPM1 AML. The safety profile observed with revumenib in this population was consistent with previously reported data. Treatment-emergent serious adverse events that occurred in ≥5% of patients included: febrile neutropenia (21%), differentiation syndrome (13%), sepsis (13%), pneumonia (8%), anemia (7%), and QTc prolongation (7%). TEAEs leading to dose reduction or treatment discontinuations occurred in 12% (10/84) and 30% (25/84) of patients, respectively.
About Mutant NPM1 (mNPM1) Acute Myeloid Leukemia (AML)
Mutations in the NPM1 gene are the most common genetic alteration in adult AML and are observed in approximately 30% of cases. Patients with relapsed or refractory mNPM1 AML have a poor prognosis and high unmet need. Similar to KMT2A-rearranged acute leukemia, mNPM1 AML is highly dependent on the expression of specific developmental genes shown to be negatively impacted by inhibitors of the menin-KMT2A interaction. mNPM1 AML is routinely diagnosed through currently available screening techniques. There are currently no approved targeted therapies for mNPM1 AML.
About Revuforj (revumenib)
Revuforj (revumenib) is an oral, first-in-class, selective menin inhibitor that is FDA approved for the treatment of relapsed or refractory (R/R) acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients one year and older.
Revumenib is in development for the treatment of R/R acute myeloid leukemia (AML) with a nucleophosmin 1 mutation (mNPM1). Positive pivotal data from the AUGMENT-101 trial in this population with revumenib as a monotherapy were recently reported and the Company submitted a supplemental NDA for revumenib in R/R mNPM1 AML in April 2025. Additionally, multiple trials of revumenib in combination with standard-of-care agents in mNPM1 AML or KMT2A-rearranged acute leukemia are ongoing or planned across the treatment landscape, including in newly diagnosed patients.
Revumenib was previously granted Orphan Drug Designation for the treatment of AML, ALL and acute leukemias of ambiguous lineage (ALAL) by the U.S. FDA and for the treatment of AML by the European Commission. The U.S. FDA also granted Fast Track designation to revumenib for the treatment of adult and pediatric patients with R/R acute leukemias harboring a KMT2A rearrangement or NPM1 mutation and Breakthrough Therapy Designation for the treatment of adult and pediatric patients with R/R acute leukemia harboring a KMT2A rearrangement.
IMPORTANT SAFETY INFORMATION
WARNING: DIFFERENTIATION SYNDROME
Differentiation syndrome, which can be fatal, has occurred with Revuforj. Signs and symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and renal dysfunction. If differentiation syndrome is suspected, immediately initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.
WARNINGS AND PRECAUTIONS
Differentiation syndrome: Revuforj can cause fatal or life-threatening differentiation syndrome (DS). Symptoms of DS, including those seen in patients treated with Revuforj, include fever, dyspnea, hypoxia, peripheral edema, pleuropericardial effusion, acute renal failure, and/or hypotension. In clinical trials, DS occurred in 39 (29%) of 135 patients treated with Revuforj. DS was Grade 3 or 4 in 13% of patients and fatal in one. The median time to onset was 10 days (range 3-41 days). Some patients experienced more than 1 DS event. Treatment interruption was required for 7% of patients, and treatment was withdrawn for 1%.
Reduce the white blood cell count to less than 25 Gi/L prior to starting Revuforj. If DS is suspected, immediately initiate treatment with systemic corticosteroids (e.g., dexamethasone 10-mg IV every 12 hours in adults or dexamethasone 0.25-mg/kg/dose IV every 12 hours in pediatric patients weighing less than 40 kg) for a minimum of 3 days and until resolution of signs and symptoms. Institute supportive measures and hemodynamic monitoring until improvement. Interrupt Revuforj if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids, or earlier if life-threatening symptoms occur such as pulmonary symptoms requiring ventilator support. Restart steroids promptly if DS recurs after tapering corticosteroids.
QTc interval prolongation: In the clinical trials, QTc interval prolongation was reported as an adverse reaction in 39 (29%) of 135 patients treated with Revuforj. QTc interval prolongation was Grade 3 in 12% of patients. The heart-rate corrected QT interval (using Fridericia’s method) (QTcF) was greater than 500 msec in 8%, and the increase from baseline QTcF was greater than 60 msec in 18%. Revuforj dose reduction was required for 5% of patients due to QTc interval prolongation. QTc prolongation occurred in 16% of the 31 patients less than 17 years old, 33% of the 88 patients 17 years to less than 65 years old, and in 50% of the 16 patients 65 years or older.
Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to treatment with Revuforj. Perform an electrocardiogram (ECG) prior to initiation of Revuforj, and do not initiate Revuforj in patients with QTcF >450 msec. Perform an ECG at least once weekly for the first 4 weeks and at least monthly thereafter. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring may be necessary. Concomitant use with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation.
Interrupt Revuforj if QTcF increases >480 msec and <500 msec, and restart Revuforj at the same dose twice daily after the QTcF interval returns to ≤480 msec
Interrupt Revuforj if QTcF increases >500 msec or by >60 msec from baseline, and restart Revuforj twice daily at the lower-dose level after the QTcF interval returns to ≤480 msec
Permanently discontinue Revuforj in patients with ventricular arrhythmias and in those who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.
Embryo-fetal toxicity: Revuforj can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Revuforj and for 4 months after the last dose of Revuforj.
ADVERSE REACTIONS
Fatal adverse reactions occurred in 4 (3%) patients who received Revuforj, including 2 with differentiation syndrome, 1 with hemorrhage, and 1 with sudden death.
Serious adverse reactions were reported in 99 (73%) patients. The most frequent serious adverse reactions (≥5%) were infection (24%), febrile neutropenia (19%), bacterial infection (17%), differentiation syndrome (12%), hemorrhage (9%), and thrombosis (5%).
The most common adverse reactions (≥20%) including laboratory abnormalities, were hemorrhage (53%), nausea (51%), phosphate increased (50%), musculoskeletal pain (42%), infection (41%), aspartate aminotransferase increased (37%), febrile neutropenia (35%), alanine aminotransferase increased (33%), parathyroid hormone intact increased (33%), bacterial infection (31%), diarrhea (30%), differentiation syndrome (29%), electrocardiogram QT prolonged (29%), phosphate decreased (25%), triglycerides increased (25%), potassium decreased (24%), decreased appetite (24%), constipation (23%), edema (23%), viral infection (23%), fatigue (22%), and alkaline phosphatase increased (21%).
DRUG INTERACTIONS
Drug interactions can occur when Revuforj is concomitantly used with:
Strong CYP3A4 inhibitors: reduce Revuforj dose
Strong or moderate CYP3A4 inducers: avoid concomitant use with Revuforj
QTc-prolonging drugs: avoid concomitant use with Revuforj. If concomitant use is unavoidable, obtain ECGs when initiating, during concomitant use, and as clinically indicated. Withhold Revuforj if the QTc interval is >480 msec. Restart Revuforj after the QTc interval returns to ≤480 msec.
SPECIFIC POPULATIONS
Lactation: advise lactating women not to breastfeed during treatment with Revuforj and for 1 week after the last dose.
Pregnancy and testing: Revuforj can cause fetal harm when administered to a pregnant woman. Verify pregnancy status in females of reproductive potential within 7 days prior to initiating Revuforj.
Pediatric: monitor bone growth and development in pediatric patients.
Geriatric: compared to younger patients, the incidences of QTc prolongation and edema were higher in patients 65 years and older.
Infertility: based on findings in animals, Revuforj may impair fertility. The effects on fertility were reversible.
To report SUSPECTED ADVERSE REACTIONS, contact Syndax Pharmaceuticals at 1-888-539-3REV or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please see Full Prescribing Information, including BOXED WARNING.