FDA Approves Revumenib for R/R Acute Leukemia With a KMT2A Translocation

This article originally appeared on OncLive^®.

The AUGMENT-101 study showed a 21.2% complete remission rate with a median duration of 6.4 months.

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The FDA has approved revumenib (Revuforj) for the treatment of adult and pediatric patients aged 1 year and older with relapsed or refractory acute leukemia and a KMT2A translocation.^1,2

Data from the phase 1/2 AUGMENT-101 study (SNDX-5613-0700; NCT04065399) showed that the menin inhibitor (n = 104) led to a complete remission (CR) plus CR with partial hematologic recovery (CRh; CR+CRh) rate of 21.2% (95% CI, 13.8%-30.3%) with a median duration of CR+CRh of 6.4 months (95% CI, 2.7-not estimable [NE]). In the patients who achieved a CR or CRh with revumenib (n = 22), the median time to response was 1.9 months (range, 0.9-5.6).

Moreover, 14% of 83 patients who were dependent on red blood cell (RBC) and platelet transfusions at baseline achieved independence during any 56-day post-baseline period, and 48% of 21 patients who were independent at baseline remained independent.

"The FDA approval of the first menin inhibitor is a major breakthrough for patients with R/R acute leukemia with a KMT2A translocation, a genetic alteration associated with a very poor prognosis," Ghayas C. Issa, MD, associate professor of leukemia at The University of Texas MD Anderson Cancer Center, stated in a news release.³ "The significant clinical benefit and robust efficacy seen with Revuforj represents a substantial improvement over what has been historically observed in these patients with previously available therapies and has the potential to be an important new treatment option for patients."

About AUGMENT-101: Eligibility, Treatment, Objectives

The single-arm cohort of an open-label, multicenter trial enrolled adult and pediatric patients at least 30 days old who had relapsed or refractory acute leukemia harboring a KMT2A translocation.² To be eligible, patients needed to have a corrected QT interval of less than 450 milliseconds. Those with an 11q23 partial tandem duplication were not permitted.

Revumenib was administered at a dose that was approximately equivalent to 160 mg in adults orally twice daily with a strong CYP3A4 inhibitor. Treatment continued until progressive disease, intolerable toxicity, failure to achieve a morphological leukemia-free state by 4 cycles of treatment, or hematopoietic stem cell transplantation.

The primary end point was CR+CRh rate.

Diving Into Demographic and Disease Characteristics

In the cohort (n = 114) median patient age was 37 years (range, 1-79), with 24% younger than 17 years. More than half of the patients (64%) were female and most were White (72%) and not Hispanic or Latino (73%). Eighty-three percent of patients had AML, 15% had acute lymphoblastic leukemia, and 2% had mixed phenotype acute leukemia.

Moreover, 22%, 19%, 10%, 10%, 7%, 3%, 2%, 2%, and 1% of patients had t(9;11), t(11;19), t(6;11), t(10;11), t(4;11), t(1;11), t(11;17), t(11;22), and t(11;16), respectively. Twenty-five percent of patients had an unknown KMT2A fusion partner. More than half of patients had relapsed/refractory disease (59%); 21% and 20% of patients had primary refractory or untreated relapsed disease.

The median number of previous regimens received was 2, with a range of 1 to 11 regimens. Forty-four percent of patients underwent prior stem cell transplantation. Fifty-three percent of patients had 1 prior relapse, 19% had 2 prior relapses, and 7% had 3 or more prior relapses.

Additional Efficacy Data

The median follow-up was 5.73 months (range, 0.3-28.9). Additional findings showed that 12.5% (95% CI, 6.8%-20.4%) of patients achieved a CR and the median duration of CR was 4.3 months (95% CI, 1.0-NE). The CRh rate was 8.7% (95% CI, 4.0%-15.8%) and the median duration of CRh was 6.4 months (95% CI, 1.9-NE).

Subgroup analysis revealed that CR+CRh was achieved in 21%, 19%, and 50% of patients with AML (n = 18/86), ALL (n = 3/16), and MPAL (n = 1/2), respectively.

Shedding Light on Safety

The safety of revumenib was examined in 104 adult patients and 31 pediatric patients with relapsed or refractory acute leukemia and a KMT2A translocation. The median duration of exposure was 2.3 months (range, <1-23).

The most common toxicities experienced by at least 20% of patients included hemorrhage (all grade, 53%; grade 3/4, 9%), nausea (51%; 4%), musculoskeletal pain (42%; 6%), infection (41%; 29%), febrile neutropenia (35%; 33%), bacterial infection (31%; 20%), diarrhea (30%; 4%), differentiation syndrome (29%; 13%), prolonged electrocardiogram QT (29%; 12%), decreased appetite (24%; 8%), constipation (23%; 1%) viral infection (23%; 4%), edema (23%; 1%), fatigue (22%; 5%), thrombosis (10%; 5%), and leukocytosis (8%; 5%).

Forty-two percent of patients experienced adverse effects (AEs) that required dose interruptions and 10% experienced AEs that led to dose reductions. Serious AEs were reported in 73% of patients and 3% experienced AEs that proved fatal (differentiation syndrome, n = 2; hemorrhage, n = 1); sudden death, n = 1).

References

1. FDA approves revumenib for relapsed or refractory acute leukemia with a KMT2A translocation. FDA. November 15, 2024. Accessed November 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-leukemia-kmt2a-translocation
2. Revuforj. Prescribing information. Syndax Pharmaceuticals, Inc.; 2024. Accessed November 15, 2024. https://cms.syndax.com/wp-content/uploads/Revuforj-full-prescribing-info.pdf
3. Syndax announces FDA approval of Revuforj (revumenib), the first and only menin inhibitor to treat adult and pediatric patients with relapsed or refractory acute leukemia with a KMT2A translocation. News release. Syndax Pharmaceuticals, Inc. November 15. 2024. Accessed November 15, 2024. https://ir.syndax.com/news-releases/news-release-details/syndax-announces-fda-approval-revuforjr-revumenib-first-and-only