Ziftomenib Combined with Venetoclax/Azacitidine in Relapsed/Refractory NPM1-m or KMT2A-r Acute Myeloid Leukemia: Interim Phase 1a Results from KOMET-007
Authors: Fathi Amir T. , Issa Ghayas C. , Wang Eunice S. , Erba Harry , Altman Jessica Kaplan , Balasubramanian Suresh Kumar , Roboz Gail J. , Schiller Gary J. , McMahon Christine M. , Palmisiano Neil D. , Juckett Mark B , Madanat Yazan F. , Rotta Marcello , Pratz Keith W. , Yaghmour George , Nadiminti Kalyan , Wei Helen , Riches Marcie , Corum Daniel , Leoni Mollie , Dale Stephen , Zeidan Amer M. 
Published: December 2024

Background: In approximately 35-40% of acute myeloid leukemia (AML) cases, leukemogenesis is driven by nucleophosmin 1 (NPM1) mutations or rearrangements in lysine methyltransferase 2A (KMT2A). Ziftomenib, a potent selective menin inhibitor, has shown clinical activity as monotherapy in adult relapsed/refractory (R/R) NPM1-mutated (NPM1-m) or KMT2A-rearranged (KMT2A-r) AML. KOMET-007, an ongoing, open-label, dose escalation (phase 1a) and expansion (phase 1b) study, aims to evaluate ziftomenib in combination with standard chemotherapies in adults with newly diagnosed and R/R NPM1-m or KMT2A-r AML (NCT05735184). Here we report interim results from phase 1a in patients with R/R AML.
Methods: Adults (age ≥18 years) with R/R NPM1-m or KMT2A-r AML were enrolled into separate dose escalation cohorts for each genotype. Following a rule-based approach, at least six dose-limiting toxicity (DLT)-evaluable patients were assigned to each cohort where ziftomenib (200, 400, or 600 mg, once daily) was escalated with standard doses of venetoclax and azacitidine (Ven/Aza). Ziftomenib was administered orally from Cycle 1 Day 8 and continuously thereafter. Primary endpoints in phase 1a were DLTs and adverse events (AEs); key secondary endpoints included composite complete remission rates (CRc; defined as complete remission [CR] or CR with partial or incomplete hematological recovery). Here we present data for the first 34 patients (pts) treated in the R/R cohorts (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 56 (range 23-86) years, and 50% were female; 41% (14/34) had NPM1-m and 59% (20/34) had KMT2A-r. Median follow-up was 35 and 14 weeks at 200 mg and 400 mg, respectively, for R/R pts with NPM1-m; and 15 and 14 weeks for those with KMT2A-r. Median number of prior therapies was 2 (range 1-8); 32% (11/34) had prior transplant; and 74% (25/34) were menin inhibitor-naive, including 68% (17/25) who had prior Ven exposure. No DLTs or ziftomenib-induced QTc prolongation were reported. The most common (≥20% of patients) grade (Gr) ≥3 treatment-emergent AEs (TEAEs) were febrile neutropenia (35%), decreased platelet count (35%), anemia (26%), decreased neutrophil count (24%), and pneumonia (24%). Gr≥3 ziftomenib- and/or backbone-related AEs occurred in 44% of patients, including decreased platelet count (18%), decreased neutrophil count (15%), and anemia (12%). On-target differentiation syndrome (DS) occurred in 12% (4/34) of R/R patients (1 NPM1-m [400 mg, Gr3] and 3 KMT2A-r [200 mg, 1-Gr3; 400 mg, 1-Gr2 and 1-Gr3]), and all cases were manageable per the DS guidance.
Twenty-four menin inhibitor-naive patients (NPM1-m, n=11; KMT2A-r, n=13) had ≥1 response assessment as of the data cutoff. Among R/R NPM1-m patients, the overall response rate (ORR) was 100% (5/5) at 200 mg and 67% (4/6) at 400 mg; CRc rates were 80% (4/5) at 200 mg and 50% (3/6) at 400 mg. In NPM1-m patients who received prior Ven, ORR was 100% (3/3) at 200 mg and 50% (2/4) at 400 mg. For R/R KMT2A-r patients, ORR was 43% (3/7) at 200 mg and 33% (2/6) at 400 mg; CRc rates were 29% (2/7) at 200 mg and 17% (1/6) at 400 mg. In KMT2A-r patients who received prior Ven, ORR was 40% (2/5) at 200 mg and 25% (1/4) at 400 mg. The study is ongoing, with 50% (7/14) of R/R NPM1-m patients (200 mg, n=4; 400 mg, n=3) and 30% (6/20) of R/R KMT2A-r patients (200 mg, n=3; 400 mg, n=3) remaining on study.
Conclusion: In the ongoing KOMET-007 study, ziftomenib combined with Ven/Aza was well tolerated at the dose levels tested to date and continued to demonstrate promising clinical activity in R/R pts. No DLTs or ziftomenib-induced QTc prolongation were reported. On-target DS occurred in 12%, including in 3 of 20 KMT2A-r patients, and all patients had resolution of DS with appropriate management. In response-evaluable, menin inhibitor-naive R/R patients, CRc rates were 80% at 200 mg and 50% at 400 mg for NPM1-m AML; and 29% and 17% for KMT2A-r AML, respectively. Clinical activity was also demonstrated in previously Ven-exposed NPM1-m and KMT2A-r patients. Based on these encouraging initial results, a dose expansion phase evaluating this triplet combination in newly diagnosed and R/R NPM1-m and KMT2A-r AML patients is underway. Updated results will be presented, as data from the 400 mg cohorts continue to mature and 600 mg cohorts are enrolling.