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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.
Fathi et al. (Tue,) studied this question.