Menin inhibitors emerge as potential new treatment option for advanced acute leukemias
Key takeaways:
- Two studies evaluating menin inhibitors showed antileukemic activity in patients who harbor certain mutations.
- Regimens for both studies are currently being investigated to determine recommended phase 2 dose.
SAN DIEGO — Researchers reported encouraging early results from novel therapies targeting menin in patients with relapsed or refractory acute leukemias harboring specific genetic alterations.
Study investigators shared the findings as part of two separate presentations at ASH Annual Meeting and Exposition.
Data from a first-in-human phase 1 study of JNJ-75276617 — a menin-KMT2A inhibitor — among adults with relapsed or refractory acute leukemia harboring KMT2A or NPM1 alterations showed an acceptable safety profile, as well as encouraging antileukemic activity.
Meanwhile, results from a phase 1/phase 2 study investigating the all-oral combination of revumenib (SNDX-5613, Syndax Pharmaceuticals) with venetoclax (Venclexta; AbbVie, Genentech) and decitabine/cedazuridine (Inqovi, Astex Pharmaceuticals, Taiho Oncology) among patients with acute myeloid leukemia showed high efficacy among those with KMT2Ar, NPM1mt or NUP98r alterations.
Additional studies are currently underway to further investigate each treatment in a more specific trial to assess efficacy for this patient population.
JNJ-75276617 for acute leukemia
Patients with relapsed or refractory acute leukemia who carry alterations in either KMT2A or NPM1 have increased risk for poor survival outcomes; preclinical studies have shown promising data regarding menin-KMT2A protein-to-protein interaction in sustaining leukemic cells with KMT2A and NPM1.
Researchers conducted a phase 1, open-label study in adults with relapsed or refractory acute leukemia who harbor KMT2A alterations or NPM1 mutations to determiee the saftey and feasibility of treatment with the investigational agent JNJ-75276617. The dose-finding study included multiple dose levels of mg or greater on either a daily or twice daily dosing schedule.
JNJ-75276617 is a potent and selective inhibitor of the interaction between the scaffolding protein menin and the methyltransferase KMT2A.
A total of 58 patients (median age, 63 years; 57% with KMT2A alteration; 43% with NPM1 alteration) received the oral agent in a dose-escalation manner on a 28-day cycle. Study participants had received a median of two prior lines of treatment.
Among the 41 patients with data eligible of evaluation, 26 experienced a reduction in bone marrow disease burden. Of those 26 patients, researchers observed a 50% or greater decrease in bone marrow blasts in 16 patients.
Among eight patients receiving the highest dosing level of at least three patients (90 mg), researchers noted an overall response rate of 50%, with responders to that specific dose level still undergoing treatment at time of data collection.
Researchers also noted that patients who received the 45 mg dose level (n = 20) had an ORR of 40%, with seven responses still ongoing as of the study’s data cutoff date.
Preliminary data among responders (n = 12) showed biologic activity via reduction in expression of menin-KMT2A target genes and induction of genes associated with differentiation. Compared with baseline, researchers noted that the percentage of KMT2A-altered cells or NPM1 variant allele frequency appeared reduced in responders (59.2% at baseline and 8.1% at post-treatment in KMT2A-altered cells by break-apart FISH probe and 13.1% at baseline and 2.8% in post-treatment in NPM1 variant allele frequency using a myeloid gene next-generation sequencing panel).
The dose-escalation trial is still ongoing, with the preferred dose yet to be determined. Researchers said the results show that treatment with JNJ-75276617 monotherapy among this patient population has an acceptable safety profile and encouraging antileukemic activity, particularly among patients with the aforementioned mutations.
“Patients with relapsed or refractory leukemias and KMT2A or NPM1 alterations often do poorly on currently available therapies, so there is a need to advance more effective options,” Elias Jabbour, MD, professor of leukemia at The University of Texas MD Anderson Cancer Center, said in a press release. “We are encouraged by the antileukemic activity of this monotherapy, which mimics what we saw in the preclinical setting.”
Revumenib combination for acute myeloid leukemia
“The interaction between menin with lysine methyltransferase 2A (KMT2A) is a dependency in acute leukemia caused by either rearrangement of the KMT2A (KMT2Ar) or nucleoporin 98 (NUP98r) genes or a mutation of the nucleophosmin 1 gene (NPM1mt),” the researchers wrote.
They said revumenib — an oral, selective inhibitor of the menin-KMT2A interaction — has demonstrated safety and clinical activity in patients with relapsed or refractory acute leukemias.
Researchers conducted a phase 1/phase 2 investigator-initiated trial with the combination treatment of revumenib, venetoclax and decitabine/cedazuridine in patients aged 12 years or older with relapsed/refractory acute myeloid leukemia.
Eight patients (median age, 27 years) enrolled in the study, with 35 mg/100 mg decitabine/cedazuridine administered orally daily on days 1-5, 400 mg venetoclax orally daily on days 1-14 and either 113 mg or 163 mg revumenib orally every 12 hours on days 1-28, with either posaconazole or voriconazole.
Researchers also planned for 1 year of maintenance therap with revumenib after hematopoietic stem cell transplantation.
Of the eight patients in the study, five had KMT2Ar, two had NUP98r and one had NPM1mt, with median prior lines of therapy of 2.5 (range, 1-4).
Seven of the eight patients had evaluable responses, with all seven attaining an ORR of 100%. Complete remission including resolution of extramedullary disease occurred in one patient, complete remission with partial hematologic recovery in one, complete remission with incomplete platelet count recovery in three, partial response in one and a reported morphologic leukemia-free state in another.
Researchers could not detect measurable residual disease in three of the seven patients at the time of data evaluation.
At the end of trial, the patients transitioned to HSCT following treatment response, with two in continued remission, one having started maintenance and one having reportedly died of transplant complications prior to starting maintenance.
Researchers noted the most common all-grade treatment-related adverse events occurring in at least 25% of patients to be febrile neutropenia (63%), hyperphosphatemia (63%), nausea (63%), and AST/ALT elevation (25%). The most common grade 3 or higher treatment-related adverse events included febrile neutropenia (63%), decreased platelet counts (25%), and decreased neutrophil counts (25%).
Early results suggest the all-oral combination has an acceptable safety and high efficacy for patients with relapsed or refractory myeloid leukemias, according to researchers. Additional research is ongoing to establish the recommended phase 2 dose and to optimize the delivery of the combination.
“These advanced and acute leukemias often are very difficult to treat and currently have no approved targeted therapies. We believe these early results suggest this treatment will be highly effective in advanced leukemias,” Ghayas C. Issa, MD, assistant professor of leukemia at The University of Texas MD Anderson Cancer Center, said in a press release. “This is our first look at an entirely oral combination therapy using menin inhibitors, and the results are very encouraging,” he added. “If sustained in further trials, this could lead to a change in the standard of care for this patient population, with great potential to improve their quality of life.”
References:
- Issa GC, et al. Abstract 216. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.
- Jabbour E, et al. Abstract 57. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.
- MD Anderson. ASH: Novel menin inhibitors show promise for patients with advanced acute myeloid leukemias (press release). Available at: https://www.mdanderson.org/newsroom/ash--novel-menin-inhibitors-show-promise-patients-advanced-acute-myeloid-leukemias.h00-159624168.html. Published Dec. 9, 2023. Accessed Jan. 17, 2024.
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