Ziftomenib Combined with Intensive Induction (7+3) in Newly Diagnosed NPM1-m or KMT2A-r Acute Myeloid Leukemia: Interim Phase 1a Results from KOMET-007
Authors: Zeidan Amer M. , Wang Eunice S. , Issa Ghayas C. , Erba Harry , Altman Jessica Kaplan , Balasubramanian Suresh Kumar , Strickland Stephen Anthony , Roboz Gail J. , Schiller Gary J. , McMahon Christine M. , Palmisiano Neil D. , Madanat Yazan F. , Rotta Marcello , Nadiminti Kalyan , Wei Helen , Riches Marcie , Corum Daniel , Leoni Mollie , Dale Stephen , Fathi Amir T. 
Published: December 2024

Background: Nucleophosmin 1 (NPM1) mutations and lysine methyltransferase 2A (KMT2A) rearrangements drive leukemogenesis in approximately 35-40% of acute myeloid leukemias (AML). Ziftomenib, a potent selective menin inhibitor, has shown clinical activity as monotherapy in adults with relapsed/refractory (R/R) NPM1-mutated (NPM1-m) or KMT2A-rearranged (KMT2A-r) AML. KOMET-007 is an ongoing, open-label, dose-escalation (phase 1a) and expansion (phase 1b) study of ziftomenib in combination with standard chemotherapies in newly diagnosed (ND) and R/R NPM1-m or KMT2A-r AML (NCT05735184). Here we report interim results from phase 1a in patients (pts) with ND AML.

Methods: Adults (age ≥18 years) with ND, high-risk NPM1-m or KMT2A-r AML were enrolled into separate dose-escalation cohorts for each genotype. High-risk disease was defined as adverse-risk cytogenetics per ELN criteria, age ≥60 years, or treatment-related AML regardless of age. Following a rule-based approach, at least six dose-limiting toxicity (DLT) evaluable pts were assigned to each cohort where ziftomenib (200, 400, or 600 mg once daily) was escalated with standard doses of cytarabine and daunorubicin (7+3). Ziftomenib was administered orally from Cycle 1 Day 8 and continuously thereafter (through induction, consolidation and continued therapy including post-transplant). Primary endpoints in phase 1a were DLTs and adverse events (AEs); key secondary endpoints included composite complete remission (CRc; defined as complete remission [CR] or CR with partial or incomplete hematological recovery) and minimal residual disease (MRD). Here we present results for the first 34 pts with ND AML (ziftomenib 200 mg, n=18; 400 mg, n=16). Enrollment in the 600 mg cohort is ongoing.

Results: As of the June 21, 2024 data cutoff, median age was 58 (range 28-74) years and 62% were female; 44% (15/34) had NPM1-m (high-risk only) and 56% (19/34) had KMT2A-r. At 200 mg and 400 mg, respectively, median follow-up was 33 and 18 weeks for ND pts with NPM1-m, and 22 and 12 weeks for those with KMT2A-r. The most common (≥20% of pts) grade ≥3 treatment-emergent AEs (TEAEs) were febrile neutropenia (56%), decreased platelet count (47%), decreased neutrophil count (38%), anemia (32%) and decreased white blood cell count (29%). Nine pts (26%) had grade ≥3 ziftomenib- or backbone-related AEs, including decreased platelet count (18%), decreased neutrophil count (15%) and anemia (9%). During continuous ziftomenib administration, in NPM1-m pts without persistent AML at end of Cycle 1, median time to neutrophil recovery (ANC ≥1K) was 33 and 28 days at 200 mg and 400 mg, respectively, and 33 and 26 days to platelet recovery (≥100K); in KMT2A-r pts, median time to neutrophil recovery was 31 and 24 days, and 28.5 and 28.5 days to platelet recovery. There were no cases of differentiation syndrome (DS), ziftomenib-associated QTc prolongation or DLTs with the 200 mg or 400 mg dose levels.

Thirty-three pts (15 with NPM1-m; 18 with KMT2A-r) had ≥1 response assessment as of the data cutoff. For NPM1-m pts, CRc rates were 100% (8/8) at 200 mg and 86% (6/7) at 400 mg, with MRD negativity among tested responders of 100% (8/8) and 80% (4/5), respectively. For KMT2A-r pts, CRc rates were 90% (9/10) at 200 mg and 63% (5/8) at 400 mg, with MRD negativity among tested responders of 83% (5/6) and 100% (3/3), respectively. The study is ongoing, with 100% (15/15) of ND NPM1-m pts (200 mg, n=8; 400 mg, n=7) and 84% (16/19) of ND KMT2A-r pts (200 mg, n=7; 400 mg, n=9) remaining on study.

Conclusion: In the ongoing KOMET-007 study, ziftomenib combined with 7+3 was well tolerated, with a consistent safety profile across dose levels, and continued to demonstrate evidence of robust clinical activity in ND pts. No DLTs or events of ziftomenib-induced QTc prolongation were reported, and rates of ziftomenib-related cytopenias were low, with no additional myelosuppression observed with the combination. Additionally, no DS events were reported at 200 mg or 400 mg, including among KMT2A-r pts, suggesting that ziftomenib can be safely combined with induction chemotherapy. In response-evaluable ND pts, CRc rate at both dose levels was 93% (14/15) for NPM1-m and 78% (14/18) for KMT2A-r. Taken together, these data support the advancement of ziftomenib in combination with intensive chemotherapy. Updated results will be presented, as data from the 400 mg cohorts continue to mature and 600 mg cohorts are enrolling.