Menin inhibitor produces excessive response charges in sure acute leukemia subtypes

Key takeaways:

• Revumenib resulted in medical responses for 53% of sufferers with KMT2A rearrangements or NPM1 mutations.
• Menin itself is a legitimate goal for remedy in each genetic subtypes of AML.

Greater than half of sufferers with two frequent acute leukemia subtypes exhibited a medical response to the investigational remedy revumenib, outcomes of the AUGMENT-101 trial confirmed.

Investigators additionally reported restricted circumstances of high-grade treatment-related toxicities amongst sufferers with superior acute leukemias with KMT2A rearrangements or NPM1 mutations who acquired revumenib (SNDX-5613, Syndax Prescription drugs) — an oral small-molecule menin inhibitor.

The newest information appeared within the journal Nature together with a separate evaluation from one other group of researchers on how leukemia cells mutate to keep away from being focused by the novel remedy.

“For the primary time, now we have proof of efficacy utilizing a menin inhibition in [patients with] KMT2A rearrangements or NPM1 mutations, with minimal toxicities,” Ghayas C. Issa, MD, medical oncologist and assistant professor within the division of leukemia at The College of Texas MD Anderson Most cancers Middle, advised Healio. “It’s a beautiful addition to our remedy arsenal that may hopefully get us to our final aim of enhancing possibilities of a treatment for a bigger variety of sufferers with acute leukemia.”

Ghayas C. Issa

Background

People with KMT2A rearrangements or NPM1 mutations make up roughly 40% of the acute leukemia inhabitants. Each leukemia subtypes are extremely immune to at the moment accessible therapies whereas missing focused therapies, in response to Issa.

“A number of scientific advances have led to the invention that the protein menin is a essential weak spot in these leukemia subtypes; subsequently, these medical research had been arrange, and our outcomes validate all of the science supporting the essential position of menin in these leukemias,” Issa stated.

Methodology

AUGMENT-101 is a first-in-human trial to judge the protection and most tolerated/really useful section 2 dose of revumenib in people with relapsed or refractory acute leukemia with KMT2A rearrangements or NPM1 mutations.

The multicenter examine comprised 68 closely pretreated sufferers (median age, 42.5 years; vary, 0.8-79; 62% ladies) divided into two parallel dose-escalation teams, together with one which acquired further robust CYP3A4 inhibitors (n = 31) and one with out further inhibitors (n = 37).

Sufferers had acquired a median of 4 traces (vary, 1-12) of earlier remedy; 46% of these handled through the examine skilled illness relapse after hematopoietic stem cell transplant.

Most examine individuals had a analysis of acute myeloid leukemia (82%), adopted by acute lymphoblastic leukemia (16%) and one affected person with mixed-phenotype acute leukemia. Forty-six sufferers (68%) had KMT2A rearrangements and 14 (21%) had NPM1 mutations.

Examine individuals acquired oral revumenib each 12 hours in steady 28-day cycles.

Median follow-up for OS was 14.3 months (95% CI, 10.6–16.7), with a knowledge cutoff date of March 31, 2022.

Key findings

Remedy with revumenib resulted in medical responses for 32 of 60 evaluable sufferers (53%).

Investigators reported full remission (CR) or CR with partial hematologic restoration in 18 of 60 sufferers (30%). Fourteen of the 18 sufferers (78%) with a CR to remedy had undetectable minimal residual illness (MRD) as decided by move cytometry.

The eight examine individuals with out NPM1 mutation or KMT2 preparations didn’t reply to remedy.

Researchers famous median OS of seven months (95% CI 4.3-11.6) and a median period of response of 9.1 months (95% CI 2.7 to not reached) amongst sufferers who achieved an preliminary CR.

Security outcomes revealed asymptomatic grade 3 prolongation of QT interval as the one dose-limiting toxicity in each examine cohorts. Investigators had anticipated this treatment-related toxicity — QT interval of better than 500 ms through electrocardiography — primarily based on the outcomes of preclinical animal research.

Dose-limiting QT prolongation occurred at dose ranges of 226 mg each 12 hours and 339 mg each 12 hours within the monotherapy remedy group and at 113 mg each 12 hours and 226 mg each 12 hours within the remedy group with further robust CYP3A4 inhibitors.

Investigators established really useful section 2 doses of revumenib of 226 mg each 12 hours and 276 mg each 12 hours within the monotherapy group and 113 mg each 12 hours and 163 mg each 12 hours within the remedy group with further robust CYP3A4 inhibitors, following a evaluate of prespecified examine protocol.

Drug resistance examine

A separate examine evaluated mechanisms of resistance to revumenib.

Investigators analyzed bone marrow samples from 31 sufferers — each responders and nonresponders — who had been handled with the agent for greater than 56 days.

The researchers discovered that 39% of sufferers grew to become immune to revumenib after creating mutations in MEN1, the gene answerable for signaling the manufacturing of the menin protein.

“These mutants attenuate drug-target binding by producing structural perturbations that influence small-molecule binding however not the interplay with the pure ligand MLL1, and forestall inhibitor-induced eviction of menin and MLL1 from chromatin,” the researchers wrote.

The outcomes provide “formal proof in sufferers that menin itself is a legitimate goal for remedy in each genetic subtypes of AML,” Scott Armstrong, MD, PhD, president of the Dana-Farber/Boston Kids’s Most cancers and Blood Issues Middle and co-senior creator of the resistance examine, stated in a press launch.

“The truth that the cell has gone by way of a lot hassle to mutate MEN1 so as to survive is a powerful indication that we’re hitting a goal the cell actually depends on,” Armstrong added.

Medical implications

The response charges seen with revumenib “are the best now we have seen with any monotherapy used for [these] resistant leukemia subsets … in sufferers handled with a number of traces of remedy,” Issa advised Healio.

That is very true for the excessive charges of residual illness clearance seen amongst remedy responders, he added.

A section 2 trial of revumenib is at the moment enrolling sufferers. The investigators and sponsor anticipate future trials of revumenib together with different therapies to deal with each leukemia subtypes and different leukemias weak to menin inhibition in varied remedy settings.

References:

For extra info:

Ghayas C. Issa, MD, may be reached atgcissa@mdanderson.org.