Monotherapy update from Phase 1 portion in Phase1/2 trial of the menin-MLL inhibitor enzomenib (DSP-5336) in patients with relapsed or refractory acute leukemia

Abstract Introduction: Enzomenib (ENZO, DSP-5336) is an investigational, oral small molecule inhibitor of the menin and KMT2A protein interaction, intentionally designed with different physiochemical properties such as short half-life of 2-5 hours, low lipophilicity and high clearance that may lead to differences in the therapeutic window and in efficacy and safety. KMT2A-rearranged (KMT2Ar), NPM1-mutated (NPM1m), and NUP98-rearranged leukemias are considered menin inhibitor sensitive, but these AML subtypes are biologically distinct with different natural histories and different degrees of menin dependency, potentially requiring different doses for optimal therapeutic effect. Updates from the ongoing Phase 1/2 study of ENZO in patients (pts) with relapsed/refractory (R/R) acute leukemia are reported. Methods: This dose-escalation/optimization study of ENZO monotherapy enrolled pts with R/R acute leukemia with KMT2Ar, NPM1m, and other HOXA9/MEIS1-driven leukemias in two arms with/without CYP3A4 inhibitor azoles. Eligibility criteria include ECOG PS ≤ 2, QTcF interval ≤ 480 msec, adequate organ function, and no active CNS leukemia. The primary phase 1 endpoints were safety and tolerability (ClinicalTrials.gov NCT04988555). Results: As of March 27, 2025, 116 pts were enrolled. Median (med) age was 54.5 yrs (12 - 89) and 62.1% were female. N=108 (93.1%) had AML and med prior regimen was 2 (1-9); 36 pts (31.0 %) had prior allogeneic stem cell transplant, 86 pts (74.1%) prior venetoclax. KMT2Ar was documented in 61 pts (52.6%), NPM1m in 34 (29.3%), and other abnormalities in 21 (17.7%). ENZO was escalated from 40 mg BID to 400 mg BID with no dose limiting toxicities (DLTs). Dose-dependent increases in exposure were observed, particularly at doses > 140 mg BID. Little to no drug accumulation was observed and azoles do not have a significant impact on exposure. Treatment related adverse events (TRAEs) in ≥10% of pts all grades were nausea (16.4%), differentiation syndrome (DS) (12.9%) and vomiting (11.2%). There was no G3+ treatment-related QT prolongation. Grade 1/2 treatment-related QT prolongation was reported in 5 pts (4.3%), did not require discontinuation and was complicated by underlying electrolyte abnormalities and concomitant medications. Grade 3 DS was reported in 8 pts (6.9%), grade 4 in 1 patient (0.8%) with TP53 mutation. DS was manageable with brief treatment interruption, corticosteroids and hydroxyurea as needed, with no deaths, study discontinuations, or dose reductions due to DS. No treatment-related deaths were observed in the study. Efficacy is reported in pts without prior menin inhibitor. For KMT2Ar with azoles (Arm B), the ORR and CR+CRh rates at the biologically effective doses of 200, 300, and 400 mg BID were 50% (3/6) and 16.7% (1/6), 72.7% (8/11) and 45.5% (5/11), and 75% (9/12) and 25% (3/12), respectively. The RP2D for pts with KMT2Ar is 300 mg BID with strong CYP3A4 inhibitor azoles. The median duration of CR+CRh at 300mg BID was not reached given ongoing remission in 4 of the 5 pts (2.3, 6.1+, 8.8+, 9.1+ and 13.2+ mos). The median time to ORR and CR+CRh at 300 mg BID were 1.1 and 1.8 mos, respectively. Med overall survival (OS) for all pts with KMT2Ar treated at ≥200 mg BID (n=29) was 11.4 mos. Dose optimization for pts with NPM1m without prior menin inhibitor is ongoing at 200 mg or 300 mg BID with strong CYP3A4 inhibitor azoles. In the 17 pts who received 200 or 300 mg BID, ORR was 58.8% (10/17) and CR+CRh was 47% (8/17). 400 mg BID in 8 pts did not improve efficacy. Median duration of CR+CRh was 5.9 months at 200 mg BID and 6.7 months at 300 mg BID as of the cut-off date. The median time to ORR and CR+CRh were 1.4 and 3.7 months in 200 mg BID and 2.7 and 3.7 months in 300 mg BID, respectively. Med OS for all pts with NPM1m treated at 200-400 mg BID (n=25) was 8.5 mo.Conclusion: ENZO has been well tolerated with no DLTs in 116 pts. ENZO has low lipophilicity and high clearance, leading to a short half-life and has demonstrated a wide therapeutic window. This may allow dosing to be tailored to the specific biology of different AML subtypes. For R/R KMT2Ar, 300 mg BID was selected as the RP2D based on clinical activity (CR+CRh rate 45.5% with durable responses) and mOS of 11.4 mos. Dose optimization is ongoing for pts with NPM1m with CR+CRh rate up to 47%, duration of CR+CRh up to 6.7 mos, and mOS of 8.5 mos observed. Updated clinical data will be presented.