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Menin Inhibitors Show Activity in AML With NPM1, KMT2A Alterations


NEW ORLEANS – Clinical trial results presented at the American Society of Hematology's annual meeting demonstrated the feasibility of using biomarker-driven approaches to personalize menin inhibitor treatment for relapsed and refractory acute myeloid leukemia patients.

In one Phase I study, dubbed AUGMENT-101, researchers led by Ghayas Issa, a leukemia specialist at MD Anderson Cancer Center, explored the activity of Syndax Pharmaceuticals' revumenib (SNDX-5613) in patients with KMT2A-rearranged or NPM1-mutant AML. Mutations in NPM1 lead to aberrant gene expression that causes leukemia, and KMT2A rearrangements are associated with an adverse prognosis leading to myeloid, lymphoid, or mixed phenotype acute leukemia which affects infants, children, and adults.

NPM1-mutated AML accounts for about 30 percent of all new AML cases in the US, affecting 6,000 patients annually. KMT2A-rearranged AML comprises 5 percent to 10 percent of new cases, affecting about 1,000 patients per year. The five-year survival rate for NPM1-mutated AML is 50 percent and 20 percent for KMT2A-rearranged AML.

Even though in recent years the field has gained a better understanding of the role these alterations play in leukemia, there are no approved, targeted therapies for AML patients with these biomarkers. Revumenib is a small molecule inhibitor of the menin-KMT2A interaction and binds to menin at the same pocket as the KMT2A wild-type and fusion proteins. That binding disrupts the aberrant gene expression and generates an anti-leukemic effect, according to Issa.

In the dose escalation study, patients received revumenib orally every 12 hours and were divided into two cohorts: one group taking strong CYP3A4 inhibitors and one not taking strong CYP3A4 inhibitors. The patients had received a median of four and as many as a dozen prior lines of therapy, and 46 percent had received a transplant.

Investigators found that menin inhibition by revumenib led to downregulation of target genes MEIS1, HOXA9, and PBX3 and increased expression of genes associated with cellular differentiation. FLT3, which is frequently co-mutated with KMT2A-rearranged or NPM1-mutated leukemia, was also downregulated.

The overall response rate in revumenib-treated patients was 53 percent, and the rate of complete remission or complete remission with partial hematologic recovery was 30 percent. The rate of MRD-negative remission among those who achieved some type of complete response was 78 percent. "This is the highest MRD-negative response we are aware of with any therapy for these leukemia subsets," said Issa.

One example of revumenib's efficacy Issa shared involved a 19-year-old patient with KMT2A-rearranged AML who had received three prior lines of therapy including two allogeneic stem cell transplants and local radiation to the spleen. After revumenib treatment, this patient achieved complete, MRD-negative remission with partial hematologic recovery. The cancer started to recede as early as the second week of treatment and there was no evidence of disease in the spleen and abdominal nodes.

"Revumenib monotherapy demonstrates deep and durable responses in heavily pretreated patients with relapsed or refractory acute leukemia with either KMT2A rearrangement or NPM1 mutation, with a manageable safety profile," said Issa.

In a second presentation at ASH, Harry Erba, director of the leukemia program within Duke University's department of medicine, provided an update on a Phase I/II first-in-human trial of Kura Oncology's menin inhibitor ziftomenib involving patients with relapsed or refractory acute myeloid leukemia. The update included data on the drug's activity in patients with KMT2A rearrangements and NPM1 and other mutations.

In the Phase I dose escalation portion of the trial, researchers evaluated ziftomenib's safety, tolerability, pharmacokinetics, and early evidence of efficacy in 30 heavily pre-treated patients with or without NPM1 and KMT2A mutations.

In the Phase Ib dose expansion part of the trial, the 200 mg dose of ziftomenib showed "reasonable efficacy" in the NPM1-mutated population, according to Erba, but those with KMT2A-rearranged disease did not respond. At the 600 mg dose, patients with NPM1 mutations had a 30 percent complete remission rate; in this subset, two-thirds also had co-mutations in IDH1/2 and FLT3. Erba noted that two patients also had RAS mutations and three patients had five or more mutations total. Out of seven patients with IDH1/2 co-mutations, 57 percent had a complete remission on ziftomenib. 

"Some have postulated that [patients with] both ASXL1 and RUNX1 mutations may also be sensitive to menin inhibition," Erba added. Although this hints that these mutations may play a significant role in patients' ability to respond to ziftomenib, Erba cautioned that the data is far from complete.

Among patients with KMT2A-rearranged AML, Erba said "significant activity" was observed with ziftomenib treatment, but only one patient out of 18 had a complete remission, translating to an overall response rate of 16.7 percent. Erba highlighted the example of a 47-year-old woman who had received many prior therapies. After two cycles of treatment, her PET scans showed obviously significant reduction in disease compared to baseline. However, using criteria for response measurement, this patient technically only achieved stable disease.

Erba concluded that ziftomenib demonstrates an encouraging safety profile and that clinical activity of the drug is optimal at 600 mg. "The activity of the [drug in the] KMT2A-rearranged population is clear and therefore optimization activities are underway to develop rational combination strategies and maximize patients' time on therapy," Erba said.