Abstract
Introduction: Venetoclax and azacitidine (VEN/AZA) is a standard backbone regimen for older/unfit patients (pts) with newly diagnosed AML and can also be administered in the relapsed or refractory (R/R) setting. Menin inhibitors are an important new class of agent in development for menin-dependent acute leukemias, such as those with KMT2A-rearrangement (KMT2Ar) or NPM1-mutation (NPM1m). Enzomenib (ENZO, DSP-5336) is an investigational, oral small molecule inhibitor of the menin-KMT2A protein interaction, intentionally designed with different physiochemical properties, such as short half-life of 2-5 hours, low lipophilicity and rapid drug clearance, that may lead to differences in the therapeutic window for safety and efficacy. ENZO monotherapy demonstrated preliminary clinical activity in pts with R/R KMT2Ar AML (CR + CRh rate 45.5% at RP2D of 300 mg BID) and R/R NPM1m AML (CR + CRh rate 47% at 200 mg or 300 mg BID), with a low and manageable rate (12.9%) of differentiation syndrome (DS). Here we report emerging new data on ENZO + VEN/AZA triplet therapy in R/R AML.
Methods: This is a Phase 1 study of ENZO in combination with VEN/AZA for adult pts with R/R KMT2Ar or NPM1m AML. Eligibility criteria include ECOG PS ≤ 2, QTcF interval ≤ 480 msec, adequate hepatic and renal function, and no active CNS leukemia. The evaluated dose levels of ENZO in combination with VEN/AZA were 140 mg, 200 mg, and 300 mg BID in a BLRM dose escalation model. VEN was administered daily for 14 days and AZA 75 mg/m2 for 7 days each 28-day cycle. ENZO was given continuously. The primary endpoints are safety, tolerability, and RP2D determination (ClinicalTrials.gov NCT04988555).
Results: 18 pts with R/R AML were enrolled to date. Median age was 50 yrs (21-76), 56% were female and median prior regimens was 2 (1-4); 3 pts (16.7 %) had prior allogeneic stem cell transplant (SCT), 6 pts (33.3%) had prior VEN, and 5 pts (27.8%) received prior menin inhibitor (2 ziftomenib, 1 revumenib, 2 enzomenib). KMT2Ar and NPM1m were documented in 7 (38.9%) and 11 (61.1%) pts, respectively.
4 pts were enrolled in the 140mg BID cohort and 7 pts each were enrolled in the 200 and 300 mg BID cohorts. There were no DLTs observed at any dose level. Treatment-related adverse events related to any agent and observed in ≥20% of pts include thrombocytopenia (44.4%), leukopenia (38.9%), lymphopenia & neutropenia (27.8% each), anemia (22.2%), and diarrhea (22.2%). DS was reported in one pt (Grade 2, onset 58 days from C1D1, resolved, remains on therapy). There were no events of QT prolongation.
Neither VEN nor ENZO exposure was significantly impacted by combination therapy. The mean time between the end of Cycle 1 and the start of Cycle 2 was 5.9 days.
In all 18 pts, the objective response rate (CR, CRi or MLFS) was 83% (15/18) and composite CR rate (CRc: CR + CRi) was 56% (10/18, 4 CR, 6 CRi). Of the 15 responders, 12 were assessed for MRD and 83% (10/12) were MRD negative by MFC or NGS. To date, only 1/15 responders (6.7%) have relapsed on study treatment: a patient with KMT2Ar who developed a recurrent FLT3-ITD mutation while on ENZO 200 mg BID with VEN/AZA (the recommended monotherapy ENZO dose for pts with KMT2Ar is 300 mg BID). In the 10 pts with CRc, 8 were assessed for MRD and 8/8 (100%) were MRD negative. In 5 pts with MLFS, 4 were assessed for MRD and 2 were MRD negative.
There were 9 pts without prior exposure to VEN or prior exposure to menin inhibitors and 100% (9/9) achieved an objective response with CRc 67% (6/9). Of those with CRc, 6/6 (100%) were MRD negative. 8/9 pts are still on treatment as of the clinical cut-off (2/2 pts with KMT2Ar [1 on maintenance post-allo], 6/7 pts with NPM1m)
Overall, 12 of 18 (66.7%) pts are still on study treatment, 2 pts went off treatment for allogeneic SCT, 2 pts for PD (both had received prior menin inhibitors), 1 pt withdrew consent (prior VEN and prior menin), and 1 pt went off study due to sepsis.
Conclusion: Preliminary data show ENZO up to 300 mg BID to be well tolerated in combination with VEN/AZA with no DLTs in 18 pts with R/R KMT2Aror NPM1m AML. No QT prolongation was reported and there was 1 report of non-serious DS. Promising preliminary clinical activity has been observed, particularly in pts without prior VEN or menin exposure (100% ORR and 67% CRc rate). There is no evidence of significant drug-drug interaction between ENZO/VEN. Enrollment continues to optimize dosing for both KMT2Ar and NPM1m AML.
