New drug casts hope for patients with refractory acute leukaemias

Revumenib, a novel potent, selective oral inhibitor of the menin-KMT2A interaction, demonstrated promising antileukaemic activity in children and adults with highly refractory acute leukaemia with KMT2Ar* or NPM1* mutation, a phase I dose-escalation study finds.

“In this first-in-human clinical trial, we provide clinical evidence of the effectiveness of menin inhibition with an oral targeted therapy, which is the first epigenetic therapy that evicts protein complexes from chromatin, leading to remissions in patients with acute leukaemia,” said the researchers.

“We found an encouraging clinical benefit, with deep molecular remissions and minimal toxicities, in a heavily pretreated population,” they continued.

In the efficacy analysis population (n=60), there was a 30-percent rate of CR/CRh**. Median time to CR/CRh was 1.9 months. Overall response*** was 53 percent. [Nature 2023;615:920-924]

Following response to revumenib, 12 participants received allogeneic SCT^# as consolidation, with nine in remission at data cutoff. “[Of these, seven] have been in remission for >6 months,” the researchers said.

There were few grade 3/4 treatment-related adverse events (TRAEs; n=11). The most frequent grade 3 TRAE was QT interval prolongation (13 percent), but all episodes resolved. “All patients with grade 3 QT prolongation were able to resume dosing at the next-lower dose level,” they noted. None discontinued revumenib due to TRAEs, and no TRAEs led to death.

Eleven patients had differentiation syndrome^##, but all were grade 2 and resolved following treatment.

 

Poor prognosis

NPM1 is the most common genetic alteration in adult AML^###. KMT2Ar occur in 80 percent of ALL^### in infants and in up to 15 percent of acute leukaemias (myeloid, lymphoid, or mixed phenotype) in children and adults. [N Engl J Med 2016;374:2209-2221; Leukemia 2021;35:2482-2495]

Patients with acute leukaemias harbouring KMT2Ar have a poor prognosis. [Nat Rev Cancer 2007;7:823-833] “The treatment of patients who have relapsed or refractory (R/R) acute leukaemia with KMT2Ar is challenging … Currently, there are no targeted therapies specifically approved for acute leukaemia with KMT2Ar or mutated NPM1,” the researchers stressed.

“The menin inhibitor revumenib has the potential to address these unmet needs,” they said.

 

Why menin inhibition?

Menin is a key oncogenic cofactor in KMT2Ar-driven leukaemias. [Cell 2005;123:207-218] Moreover, other leukaemia genotypes have shown susceptibility to menin inhibition. [Blood 2022;139:894-906; Leukemia 2021;35:1405-1417] “Therefore, menin inhibitors have the potential to reach a larger subset of acute leukaemia with similar dependency on the menin-KMT2A interaction, which could be identified using precision approaches testing characteristic gene expression,” said the researchers.

In AML with NPM1 mutation, HOX- and MEIS1-mediated leukaemogenic transcription result from the interaction between menin and wild-type KMT2A. [Cancer Discov 2016;6:1166-1181; Science 2020;367:586-590] “[Blocking] the menin-KMT2A interaction disrupts the assembly of oncogenic KMT2A wild-type or fusion complexes on chromatin,” they said.

The study enrolled 68 patients and had two parallel dose-escalation cohorts – one with (n=31) and another without (n=37) strong CYP3A4 inhibitors. Revumenib was administered orally Q12H in continuous 28-day cycles.

Fifty-six patients had R/R AML, 11 had ALL, and one had mixed-phenotype acute leukaemia. Forty-six patients had KMT2Ar and 14 had mutated NPM1. There were 60 adults (median age 50.5 years) and eight children or adolescents (median age 2.5 years). Patients had a median four prior lines of therapy, and about half relapsed after allogenic SCT.

“[Taken together, our] data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes,” the researchers said.

The US FDA has granted Breakthrough Therapy Designation for revumenib for R/R KMT2Ar acute leukaemia in adult and paediatric patients. [www.prnewswire.com/news-releases/syndax-announces-us-fda-breakthrough-therapy-designation-granted-for-revumenib-for-the-treatment-of-adult-and-pediatric-patients-with-relapsed-or-refractory-kmt2a--rearranged-mllr-acute-leukemia-301694253.html, accessed May 1, 2023]

A phase II study is underway to further validate the potential of revumenib in this setting. [www.cancer.gov/news-events/cancer-currents-blog/2023/revumenib-menin-inhibitor-advanced-aml, accessed May 1, 2023]