Menin Inhibitors: A Promising Class of Targeted Therapies for KMT2A-rearranged and NPM1-mutated Acute Leukemias

Study Title: A Phase 1/2 Study of SNDX-5613 in Relapsed/Refractory Leukemias, Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 mutation (AUGMENT-101)

ClinicalTrials.gov Identifier: NCT04065399

Sponsor: Syndax Pharmaceuticals, Inc.

Participating Centers: Currently 16 sites in the United States, as well as several sites in Australia, Canada, and the Netherlands

Accrual Goal: 222 patients in the phase II portion

Study Design: AUGMENT-101 is a prospective, multicenter phase I/II dose-escalation and expansion study investigating SNDX-5613 in adult and pediatric patients with relapsed/refractory KMT2A-rearranged (KMT2Ar) or NPM1-mutated acute leukemia. The primary objective of the phase I portion is to identify the maximum-tolerated dose (MTD) and the recommended phase II dose (RP2D). The objective of the phase II portion is to assess the safety and efficacy of SNDX-5613 in three cohorts: 1) KMT2Ar acute lymphocytic leukemia (ALL) or mixed-phenotype acute leukemia; 2) KMT2Ar acute myeloid leukemia (AML); and 3) NPM1-mutated AML.

Study Title: A Phase 1/2A First in Human Study of the Menin-MLL Inhibitor KO-539 in Patients with Relapsed or Refractory Acute Myeloid Leukemia (KO-MEN-001)

ClinicalTrials.gov IDENTIFIER: NCT04067336

Sponsor: Kura Oncology, Inc.

Participating Centers: 26 sites in the United States, France, and Spain

Accrual Goal: Approximately 60 patients in the phase I portion, more in the phase II expansion cohorts

Study Design: KO-MEN-001 is a multicenter, international, phase I/IIA study of the menin inhibitor KO-539 (ziftomenib). The study includes adults 18 years and older with relapsed/refractory AML. The phase IA dose escalation portion included any patients with relapsed/refractory AML, while the phase IB dose-validation/expansion portion includes patients with KMT2Ar or an NPM1 mutation. The objectives are to determine the MTD and RP2D and to assess the safety and tolerability of KO-539. A phase II portion assessing tolerability and efficacy in patients with KMT2Ar and NPM1 mutations is also planned.

Rationale: Rearrangements of the KMT2A gene (also known as MLL1) occur in five to 10 percent of acute leukemias and are particularly common in infant leukemia (70% to 80%).^1-3  More than 80 fusion partners of KMT2A have been identified.⁴  KMT2Ar mutations are associated with a poor prognosis due to increased resistance to chemotherapy and higher rates of relapse^5,6 ,; KMT2Ar leukemias are characterized by the aberrant overexpression of HOX genes.^{7, 8}  The discovery that the cofactor menin is necessary for KMT2A to bind HOX gene promoters led to the development of small-molecule inhibitors that target the KMT2A-menin interaction.⁹  Preclinical studies of these agents demonstrated inhibition of KMT2A-driven leukemias and efficacy in mouse models.^10-13  NPM1-mutated AML has a gene expression profile similar to KMT2Ar leukemias with upregulation of HOX genes, and laboratory studies have demonstrated that targeting the menin-KMT2A interaction is also effective in these AMLs.^{3, 13-15}  Of note, other leukemias overexpressing HOX genes (e.g., NUP98-rearranged AML) may also respond to menin inhibitors.¹⁶ 

At least four different menin inhibitors have now been developed for clinical use, including SNDX-5613 and KO-539, and multiple clinical trials are underway.³  Phase I data from AUGMENT-101 (NCT04065399) were presented at the 2021 ASH Annual Meeting.¹⁷  The study initially enrolled pediatric or adult patients with any relapsed and/or refractory acute leukemia with the primary objectives of assessing safety, tolerability, and the RP2D of SNDX-5613. The protocol was subsequently amended to focus on patients with KMT2Ar or NPM1-mutated acute leukemia. SNDX-5613 was well-tolerated. After 59 subjects had enrolled, the most common adverse events included QTc prolongation (78% any grade), nausea (27%), vomiting (17%), and diarrhea (12%). Grade 1/2 differentiation syndrome was reported in 14 percent (8 of 59 patients). Among patients with KMT2Ar leukemia, the overall response rate (ORR) was 61 percent (23 of 38 patients), with a complete remission (CR) or CR with partial hematologic recovery (CRh) rate of 24 percent (9 of 38 patients). In patients with an NPM1 mutation, the ORR was 38 percent (5 of 13 patients), with a CR/CRh rate of 23 percent (3 of 13 patients). The median duration of response had not yet been reached. This study is ongoing, and the phase II portion will assess tolerability and efficacy in KMT2Ar AML and ALL as well as NPM1-mutated AML.

Early phase I data from the KO-MEN-001 (NCT04067336) study of KO-539 (now named ziftomenib) in patients with relapsed/refractory AML have also been presented.¹⁸  At the time of the 2020 ASH Annual Meeting presentation, 12 subjects had enrolled. Doses up to 400 mg daily were evaluated, and dose escalation was still ongoing. No dose-limiting toxicities had been observed. Of six patients evaluable for response, two achieved a CR, and one achieved a morphologic leukemia-free state. This study is ongoing, with plans for the phase II portion to focus on patients with KMT2Ar or NPM1-mutated leukemias.

Comment: Menin inhibitors represent a promising and very important clinical development. To date, these agents appear to be most effective for KMT2Ar and NPM1-mutated acute leukemias, though it is possible that a subset of leukemias with other genetics may respond as well. The ongoing studies of SNDX-5613 and KO-539 will assess tolerability and response rates in patients with KMT2Ar and NPM1-mutated leukemias. KMT2Ar-driven leukemias in particular have a poor prognosis and represent a huge clinical need. It will also be important to study menin inhibitors in patients with relapsed AML with NPM1 and FLT3-ITD comutations, as responses to FLT3 inhibitors alone are often not durable. Trials combining menin inhibitors with standard induction chemotherapy and venetoclax-based regimens for both newly diagnosed and relapsed/refractory AML are also being developed, and results from the ongoing and planned studies are eagerly awaited.

Dr. McMahon indicated no relevant conflicts of interest.