Update on a Phase 1/2 First-in-Human Study of the Menin-KMT2A (MLL) Inhibitor Ziftomenib (KO-539) in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Histone-lysine-N-methyltransferase 2A (KMT2A) is a central regulator of target genes that drive leukemogenic transformation. KMT2A rearrangements (KMT2Ar) and nucleophosmin 1 mutations (NPM1m), founding events in leukemia, occur in 5-10% and 30% of acute myeloid leukemia (AML) patients (pts), respectively. KMT2Ar functions in a protein complex that requires menin to cause epigenetic dysregulation in AML. KMT2Awt-menin also cooperates with NPM1m causing dysregulation of an overlapping set of leukemogenic genes dependent on KMT2A-menin interaction. Thus, the strong rationale for targeting menin in KMT2Ar/NPM1m AML.

We present here preliminary KOMET-001 (NCT04067336) data, an ongoing Phase (P) 1/2 study of ziftomenib (KO-539), an inhibitor of KMT2A-menin interaction, in adult pts with relapsed/refractory (R/R) AML. Ziftomenib is dosed orally, once daily, in 28-day cycles.

P1a dose escalation enrolled 30 adult pts with R/R AML regardless of genotype. Pts received 50-1000 mg ziftomenib to assess safety, tolerability, pharmacokinetics, and anti-leukemic activity. Median age was 65.5 years (range [r] 22-85); 33%/13% had KMT2Ar/NPM1m AML. Pts had a median of 3 prior therapies (r 1-10), with 17% having ≥ 1 prior stem cell transplant (SCT).

In P1a, treatment-emergent adverse events (TEAEs) ≥ Grade (Gr) 3 in ≥ 10% of all pts (N=30) were anemia, pneumonia (27%); neutropenia (17%); thrombocytopenia (13%); febrile neutropenia, decreased appetite (10%). Two dose-limiting toxicities (DLTs) occurred: pneumonitis (400 mg) and differentiation syndrome (DS, 1000 mg); per protocol, the DLT in 1/1 pt at 1000 mg resulted in de-escalation.

Clinical benefit with disease control (eg, decreasing blast counts [BC] or hydroxyurea requirement) occurred across dose levels. At 100 mg, 1 complete remission (CR) was observed in a pt with SETD2, RUNX1 mutations. At 200 mg, the 2 NPM1m pts responded (1 experienced a CR without measurable residual disease [MRD-] with >100 weeks duration (ongoing), and 1 had morphologic leukemic-free state [MLFS]). At 600 mg, 1 of 2 KMT2Ar pts had stable disease with significantly decreased BC lasting >4 months.

P1b dose-validation explored 2 P1a doses (200/600 mg) in 24 pts with KMT2Ar/NPM1m AML to determine an optimal biologically active dose. KMT2Ar/NPM1m pts randomized to 200/600 mg were 9/3 and 6/6. Median age was 46 years (r 31-82), and 33% had ≥1 prior SCT. The 200/600mg pts had a median of 2.5/4 prior therapies (r 1-12/2-8).

In P1b, TEAEs ≥ Gr 3 in ≥ 10% of all pts (N=24) were anemia, febrile neutropenia, neutropenia, thrombocytopenia (25% each); DS, leukocytosis (17% each); sepsis, leukopenia (13% each). At 200 mg (N=12), TEAEs ≥ Gr 3 in ≥ 10% were neutropenia, thrombocytopenia (33% each); febrile neutropenia, anemia, sepsis (25% each); DS, leukocytosis, respiratory failure (17% each). At 600 mg (N=12), TEAEs ≥ Gr 3 in ≥ 10% were febrile neutropenia, anemia (25% each); DS, leukocytosis, neutropenia, thrombocytopenia, leukopenia, diarrhea (17% each).

The on-target effect of DS occurred in 7 P1b pts. At 200 mg, 3 were KMT2A pts, of which 2 had events ≥ Gr 3 including 1 death. Of the 4 pts at 600 mg, 2 were Gr 3 (1 each KMT2A/NPM1), and 2 were Gr 2 (1 each KMT2A/NPM1). Since implementation of DS Guidance, reported DS event severity has declined.

P1b clinical efficacy was dose-dependent. At 200 mg, changes in bone marrow (BM) morphology and stable/decreasing BC were seen. Three pts were dose-escalated to 600 mg with improvement: 1 achieved a BM BC < 5% and significant reduction of high burden extramedullary disease despite persistence of a small disease focus; 1 had significantly reduced BC and disease control; 1 attained MLFS and remains on treatment. At 600 mg, 25% of P1b pts had a best response of CR/CR with partial hematologic recovery (CRh); 33.3% of NPM1m pts achieved CR/CRh. Composite CR was 33% with 75% MRD-. Overall response rate (ORR) was 42%. Pts who experienced DS had an ORR of 75%. At data cutoff, 50% of pts remain on treatment.

Overall, P1a results demonstrated a manageable safety profile and preliminary efficacy that informed the P1b doses to determine the optimal biologically active dose. P1b results suggest that with appropriate DS management, ziftomenib is well tolerated. Additionally, the 600 mg dose demonstrates meaningful signs of efficacy in heavily pretreated R/R AML pts, warranting further investigation of ziftomenib as a monotherapy and in combination with rational therapeutic partners.