Menin inhibitors are making inroads in the treatment of acute myeloid leukemia (AML). These drugs selectively target KMT2A-rearranged or NPM1-mutant AML, and early studies suggest they will be a welcome addition for patients with these aberrations. KMT2A rearrangements occur in about 5% of patients with AML, and NPM1 mutations occur in about 30% of newly diagnosed patients with AML. Currently, there are no approved therapies for these targets.

At the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition, two different abstracts presented early data on two investigational menin inhibitors—revumenib (SNDX-5613) and ziftomenib (KO-539)—in relapsed or refractory AML.^1,2 Preliminary data are encouraging, and both drugs will be studied further as monotherapy and in combination.

Revumenib

Revumenib is a potent selective inhibitor of the menin-KMT2A interaction. Updated results of a first-in-human phase I trial described safety, pharmacokinetics, pharmacodynamics, and efficacy of monotherapy with revumenib in patients with relapsed or refractory AML, including those with KMT2A-rearranged or NPM1-mutant AML.¹

“KMT2A rearrangements are associated with an adverse prognosis in AML,” said presenting author Ghayas C. Issa, MD, of The University of Texas MD Anderson Cancer Center, Houston.

The trial had a rolling design, with oral revumenib given every 12 hours on a continuous dosing schedule. The safety analysis included 60 adult and 8 pediatric patients. Of them, eight patients did not have KMT2A rearrangements. Almost two-thirds (62%) were female. A total of 2 patients were still in ongoing treatment at the time of the presentation, and 12 proceeded to transplantation while in remission.

“The complete response or complete response with incomplete hematologic recovery rate [with revumenib] was highly promising, at 30%.”

— GHAYAS C. ISSA, MD

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Revumenib was reported to be well tolerated. A total of 53% had QT prolongation as a treatment-related adverse event, and 13% of them were grade 3. Differentiation syndrome was reported in 16% and was successfully managed with steroids.

“The complete response or complete response with incomplete hematologic recovery rate was highly promising, at 30%. The overall response rate was 53%, and 78% achieved measurable residual disease–negative status. “These rates are the highest we are aware of,” Dr. Issa stated.

Among those with KMT2A rearrangements, the overall response rate was 59%, and the complete response or complete response with incomplete hematologic recovery rate was 33%.

“Revumenib achieved rapid and durable responses,” Dr. Issa continued. The median time to complete response or complete response with incomplete hematologic recovery was 1.9 months, and the duration of response in those who achieved this milestone was 9.1 months. A total of 38% proceeded to transplantation.

Median overall survival was 7 months. “We would expect a median overall survival of about 3 months in this population,” Dr. Issa told the audience.

There was an intriguing suggestion of response in a small number of patients previously treated with a FLT3 inhibitor. “Treatment was associated with downregulation of FLT3 expression, which is likely an off-target effect. Responses were also seen in bone and extramedullary sites,” he noted.

Patients are continuing to enroll in the phase II study of monotherapy, called AUGMENT-101. AUGMENT-102 will study revumenib in combination with chemotherapy in relapsed or refractory AML.

Ziftomenib

The second abstract focused on 53 patients enrolled in the KOMET-001 phase Ib trial of ziftomenib in relapsed or refractory AML with KMT2A rearrangements or NPM1 mutations.²

“We saw no patterns of toxicity according to dose and no evidence of QTc prolongation,” stated lead author Harry P. Erba, MD, PhD, of Duke University Medical Center. “Ziftomenib has an encouraging safety profile and tolerability. The reported events are consistent with features of the underlying disease. Differentiation syndrome is an on-target effect that has been manageable with a mitigation strategy,” he said.

“We saw no patterns of toxicity according to dose and no evidence of QTc prolongation [with ziftomenib].”

— HARRY P. ERBA, MD, PhD

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In phase Ib, 53 patients were randomly assigned to the lowest effective doses of ziftomenib identified in phase Ia, 200 mg (n = 17), or 600 mg (n = 36). The median number of prior therapies was three. There were no adverse events above grade 3 in the NPM1 cohort. A total of 25% reported differentiation syndrome, and 10% had febrile neutropenia. In the KMT2A cohort, about 38% reported differentiation syndrome.

“We believe the difference in the KMT2A patients is a greater risk of extramedullary disease, as well as high levels of ziftomenib tissue penetration, leading to an atypical presentation of differentiation syndrome. With experience, we have been able to reduce the incidence of differentiation syndrome,” Dr. Erba noted.

“Both dose levels showed consistent blast reduction. However, many of the KMT2A-rearrangedpatients were not on the drug long enough to determine response,” he added.

At data cutoff, 30% of patients on 600 mg were in ongoing treatment. “The data support a 600-mg dose as the recommended phase II dose,” Dr. Erba reported.

Dr. Erba continued: “In NPM1-mutated patients, there is a robust data set demonstrating substantial clinical benefit with a 30% complete response rate in 20 NPM1-mutated AML patients. This is encouraging. The recommended dose for NPM1-mutated AML is 600 mg. There are plans to study this drug upfront in combination with intensive and less intensive therapies. However, the expansion cohort will include relapsed/refractory NPM1-mutated patients treated with ziftomenib as a single agent.”

“The monotherapy data are supportive of combination strategies for patients with KMT2A-rearranged AML in the planned phase II study,” he added. 

DISCLOSURE: Syndax is developing revumenib, and Kura Oncology is developing ziftomenib. Dr. Issa reported financial relationships with Novartis, Kura Oncology, Nuprobe, Celgene, Syndax, Merck, Cullinan, and Novartis. Dr. Erba reported financial relationships with Gilead/Forty Seven, Forma Therapeutics, Kura Oncology, Trillium, Janssen Oncology, Daiichi Sankyo, ImmunoGen, Glycomimetics, Jazz Pharmaceuticals, Incyte, MacroGenics, Novartis, Pfizer, PTC Therapeutics, Takeda, Celgene, Astellas, Amgen, Agios, and AbbVie.

REFERENCES

1. Issa GC, Aldoss I, DiPersio J, et al: The menin inhibitor SNDX-5613 (revumenib) leads to durable responses in patients with KMT2A-rearranged or NPM1-mutant AML: Updated results of a phase 1 study. 2022 ASH Annual Meeting and Exposition. Abstract 63. Presented December 10, 2022.

2. Erba HP, Fathi AT, Issa GC, et al: Update on a phase 1/2 first-in-human study of the menin-KMT2A inhibitor ziftomenib (KO-539) in patients with relapsed or refractory acute myeloid leukemia. 2022 ASH Annual Meeting and Exposition. Abstract 64. Presented December 10, 2022.