Menin inhibitor produces high response rates in certain acute leukemia subtypes
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Key takeaways:
- Revumenib resulted in clinical responses for 53% of patients with KMT2A rearrangements or NPM1 mutations.
- Menin itself is a valid target for therapy in both genetic subtypes of AML.
More than half of patients with two common acute leukemia subtypes exhibited a clinical response to the investigational therapy revumenib, results of the AUGMENT-101 trial showed.
Investigators also reported limited cases of high-grade treatment-related toxicities among patients with advanced acute leukemias with KMT2A rearrangements or NPM1 mutations who received revumenib (SNDX-5613, Syndax Pharmaceuticals) — an oral small-molecule menin inhibitor.
The latest data appeared in the journal Nature along with a separate analysis from another group of researchers on how leukemia cells mutate to avoid being targeted by the novel therapy.
“For the first time, we have evidence of efficacy using a menin inhibition in [patients with] KMT2A rearrangements or NPM1 mutations, with minimal toxicities,” Ghayas C. Issa, MD, medical oncologist and assistant professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, told Healio. “It’s a wonderful addition to our treatment arsenal that will hopefully get us to our ultimate goal of improving chances of a cure for a larger number of patients with acute leukemia.”
Background
Individuals with KMT2A rearrangements or NPM1 mutations make up approximately 40% of the acute leukemia population. Both leukemia subtypes are highly resistant to currently available therapies while lacking targeted therapies, according to Issa.
“Multiple scientific advances have led to the discovery that the protein menin is a critical weakness in these leukemia subtypes; therefore, these clinical studies were set up, and our results validate all the science supporting the critical role of menin in these leukemias,” Issa said.
Methodology
AUGMENT-101 is a first-in-human trial to evaluate the safety and maximum tolerated/recommended phase 2 dose of revumenib in individuals with relapsed or refractory acute leukemia with KMT2A rearrangements or NPM1 mutations.
The multicenter study comprised 68 heavily pretreated patients (median age, 42.5 years; range, 0.8-79; 62% women) divided into two parallel dose-escalation groups, including one that received additional strong CYP3A4 inhibitors (n = 31) and one without additional inhibitors (n = 37).
Patients had received a median of four lines (range, 1-12) of previous therapy; 46% of those treated during the study experienced disease relapse after hematopoietic stem cell transplant.
Most study participants had a diagnosis of acute myeloid leukemia (82%), followed by acute lymphoblastic leukemia (16%) and one patient with mixed-phenotype acute leukemia. Forty-six patients (68%) had KMT2A rearrangements and 14 (21%) had NPM1 mutations.
Study participants received oral revumenib every 12 hours in continuous 28-day cycles.
Median follow-up for OS was 14.3 months (95% CI, 10.6–16.7), with a data cutoff date of March 31, 2022.
Key findings
Treatment with revumenib resulted in clinical responses for 32 of 60 evaluable patients (53%).
Investigators reported complete remission (CR) or CR with partial hematologic recovery in 18 of 60 patients (30%). Fourteen of the 18 patients (78%) with a CR to therapy had undetectable minimal residual disease (MRD) as determined by flow cytometry.
The eight study participants without NPM1 mutation or KMT2 arrangements did not respond to therapy.
Researchers noted median OS of 7 months (95% CI 4.3-11.6) and a median duration of response of 9.1 months (95% CI 2.7 to not reached) among patients who achieved an initial CR.
Safety results revealed asymptomatic grade 3 prolongation of QT interval as the only dose-limiting toxicity in both study cohorts. Investigators had anticipated this treatment-related toxicity — QT interval of greater than 500 ms via electrocardiography — based on the results of preclinical animal studies.
Dose-limiting QT prolongation occurred at dose levels of 226 mg every 12 hours and 339 mg every 12 hours in the monotherapy treatment group and at 113 mg every 12 hours and 226 mg every 12 hours in the treatment group with additional strong CYP3A4 inhibitors.
Investigators established recommended phase 2 doses of revumenib of 226 mg every 12 hours and 276 mg every 12 hours in the monotherapy group and 113 mg every 12 hours and 163 mg every 12 hours in the treatment group with additional strong CYP3A4 inhibitors, following a review of prespecified study protocol.
Drug resistance study
A separate study evaluated mechanisms of resistance to revumenib.
Investigators analyzed bone marrow samples from 31 patients — both responders and nonresponders — who had been treated with the agent for more than 56 days.
The researchers found that 39% of patients became resistant to revumenib after developing mutations in MEN1, the gene responsible for signaling the production of the menin protein.
“These mutants attenuate drug-target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin,” the researchers wrote.
The results offer “formal proof in patients that menin itself is a valid target for therapy in both genetic subtypes of AML,” Scott Armstrong, MD, PhD, president of the Dana-Farber/Boston Children's Cancer and Blood Disorders Center and co-senior author of the resistance study, said in a press release.
“The fact that the cell has gone through so much trouble to mutate MEN1 in order to survive is a strong indication that we’re hitting a target the cell truly relies on,” Armstrong added.
Clinical implications
The response rates seen with revumenib “are the highest we have seen with any monotherapy used for [these] resistant leukemia subsets ... in patients treated with multiple lines of therapy,” Issa told Healio.
This is especially true for the high rates of residual disease clearance seen among treatment responders, he added.
A phase 2 trial of revumenib is currently enrolling patients. The investigators and sponsor anticipate future trials of revumenib in combination with other therapies to treat both leukemia subtypes and other leukemias vulnerable to menin inhibition in various treatment settings.
References:
- Dana-Farber Cancer Institute. Study unravels a cause of resistance to novel drug in patients with acute leukemia (press release). Available at: www.dana-farber.org/newsroom/news-releases/2023/study-unravels-a-cause-of-resistance-to-novel-drug-in-patients-with-acute-leukemia/. Published March 15, 2023. Accessed March 15, 2023.
- Issa GC, et al. Nature. 2023;doi:10.1038/s41586-023-05812-3.
- Perner F, et al. Nature. 2023;10.1038/s41586-023-05755-9.
For more information:
Ghayas C. Issa, MD, can be reached atgcissa@mdanderson.org.
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