The menin inhibitor revumenib produced complete remissions (CR) or complete remissions with a partial hematologic recovery (CRh) in 30% of patients with KMT2A-rearranged (KMT2Ar) or NPM1-mutant leukemia, according to a phase I study in which the drug was evaluated in humans for the first time. The study results were published in Nature.
The therapy could help fill an important treatment gap, researchers said.
“This response rate is the highest seen with any therapy in this setting for relapsed or refractory [R/R] KMT2Ar leukemias and is similar to what has been observed, for example, with IDH [isocitrate dehydrogenase] inhibition,” said lead author Ghayas Issa, MD, of MD Anderson Cancer Center in Houston. Seventy-eight percent of those with a CR or CRh were negative for measurable residual disease, which Dr. Issa said was an even more impressive result, though he cautioned that the findings need to be further evaluated in the phase II trial, which is underway.
Patients with these leukemia subtypes are prone to resistance and there are no approved therapies that specifically target them, Dr. Issa noted.
“Leukemias caused by KMT2A-rearrangement are associated with resistance to currently available therapies, whether they occur in infants, children, or adults and regardless of phenotype – lymphoid or myeloid,” Dr. Issa said. Also, he noted that recent findings by his group showed R/R acute myeloid leukemia (AML) involving NPM1 mutations is “as bad as any other [R/R] AML.”
Revumenib is an oral therapy that disrupts the interaction between KMT2A and menin, without which the chromatin complex responsible for leukemia gene expression and cell-differentiation arrest cannot survive. This allows the leukemia cells to differentiate into normal cells, creating an antileukemic effect.
Between 2019 and 2022, 37 patients were enrolled in a dose-escalation arm of revumenib without cytochrome P450 3A4 (CYP3A4) inhibitors and 31 in a dose-escalation arm with CYP3A4 inhibitors. The arm with CYP3A4 inhibitors was included because revumenib is a substrate of CYP3A4. The patients had a median of four previous lines of treatment (range = 1-12), and 46% had relapsed after an allogeneic hematopoietic cell transplant.
Patients with acute leukemia were initially allowed to enroll without regard to cytogenetic or mutational profile, but an early amendment was made to limit enrollment to those with KMT2A-rearrangment or NPM1 mutations.
Of the 46 patients with KMT2A-rearrangements, 33% had a CR or CRh. The median time to CR or CRh was 1.9 months, and those with a CR or CRh had a median duration of response of 9.1 months. Just 32% of patients overall had no response to the therapy.
The median overall survival (OS) was 7.0 months, researchers reported. Historically, in adult patients with KMT2A-rearrangements with at least two prior lines of therapy, the OS was less than three months, so this represents an improvement, Dr. Issa said, although he cautioned again that the phase II results need to be evaluated.
The only toxicity found to be dose-limiting was grade 3 prolonged QT interval (over 500 ms), seen in six patients who were able to resume dosing at the next-lower dose. Sixty-seven patients (99%) experienced an adverse event during treatment with revumenib, while 53 patients (78%) experienced a treatment-related adverse event (TRAE) of any grade. Overall, the most common TRAEs were prolonged QT interval (56%), nausea (50%), vomiting (40%), and febrile neutropenia (31%).
Mutations conferring resistance have been seen at a relatively high rate for an epigenetic therapy, Dr. Issa said, which points to the aggressive nature of the leukemia and to the crucial role of the KMT2A-menin interaction.
“We are still learning how to overcome these mutations,” he said. “One possibility could be combining menin inhibition with other therapies.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Issa GC, Aldoss I, DiPersio J, et al. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature. 2023 Mar;615(7954):920-924.
Perspectives
Despite the availability of multiple targeted agents for AML, more than half of patients have disease lacking “actionable” mutations and therefore receive conventional chemotherapy with often suboptimal outcomes. Menin inhibitors constitute a new genre of agents targeting the underlying biology of nucleophosmin (NPM1)-mutant and KMT2A (formerly known as MLL1)-rearranged (KMT2Ar) acute leukemias.1 Revumenib (SNDX-5613) is a potent oral inhibitor of the interaction between menin and KMT2A proteins driving leukemogenesis in these disease subtypes.2,3
This phase I study of revumenib monotherapy yielded a low but clinically meaningful CR rate of 30% in patients with heavily pretreated multiply R/R acute leukemia. These response rates parallel those achieved with other approved single-agent targeted therapies in the relapsed setting (i.e., gilteritinib, ivosidenib, enasidenib). Given its mechanism of action, the low incidence (16%) and mild toxicity (grade 2) of revumenib-induced differentiation syndrome (DS) was somewhat surprising.4 However, many questions regarding revumenib still remain: Is there a difference in efficacy between the two genetic subtypes? Acute lymphoblastic leukemia versus AML? Pediatric versus adult patients? If QT prolongation had not limited further dose escalation, would higher doses of revumenib have resulted in improved efficacy or DS? Of note, regulatory approval of another targeted agent, quizartinib, for relapsed AML was waylaid by similar cardiac concerns.5
These results are the first to validate menin inhibition as an effective clinical strategy for specific leukemia subsets. Ultimately, revumenib may be most effective in combinatorial regimens both to enhance responses and prevent emergence of menin-resistant mutations.6 Among the most captivating therapeutic partners for revumenib are FLT3 and IDH1/2 inhibitors, as FLT3 and IDH1/2 are frequently co-mutated with NPM1 and KMT2Ar. Most encouragingly, revumenib is the first of many menin inhibitors in clinical development.1 In a phase I/II study, ziftomenib (KO-539) resulted in a 30% CR rate in patients with NPM1-mutant relapsed AML with more potent but manageable DS.7 The exciting results of this phase I revumenib trial provide hope that a new class of targeted therapies for acute leukemia is on the horizon.4
Eunice S. Wang, MD
Roswell Park Comprehensive Cancer Center,
Buffalo, New York
References
- Swaminathan M, Bourgeois W, Armstrong SA, Wang ES. Menin inhibitors in acute myeloid leukemia-what does the future hold? Cancer J. 2022;28(1):62-66.
- Krivtsov AV, Evans K, Gadrey JY, et al. A menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia. Cancer Cell. 2019;36(6):660-673.e611.
- Uckelmann HJ, Kim SM, Wong EM, et al. Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia. Science. 2020;367(6477):586-590.
- Issa GC, Aldoss I, DiPersio J, et al. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature. 2023;615(7954):920-924.
- Cortes JE, Khaled S, Martinelli G, et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019;20(7):984-997.
- Perner F, Stein EM, Wenge DV, et al. MEN1 mutations mediate clinical resistance to menin inhibition. Nature. 2023;615(7954):913-919.
- Erba HP, Fathi AT, Issa GC, et al. Update on a phase 1/2 first-in-human study of the menin-KMT2A (MLL) inhibitor ziftomenib (KO-539) in patients with relapsed or refractory acute myeloid leukemia. Blood. 2022;140 (suppl 1):153-156.
