Rapid Readout: Safety and Efficacy of Menin Inhibition in Patients with MLL-Rearranged and NPM1 Mutant Acute Leukemia: SNDX-5613

OncLive® Rapid Readout from Safety and Efficacy of Menin Inhibition in Patients with MLL-Rearranged and NPM1 Mutant Acute Leukemia: SNDX-5613

Segment Description: Eytan Stein, MD, discusses the AUGMENT-101 trial and menin inhibition in patients with MLL-rearranged and NPM1 mutant acute leukemia, which was presented at the 63rd ASH Annual Meeting in 2021. (Abstract 699)

Segment Body Content:

• Translocations involving the MLL gene on chromosome 11q23 result in fusions with ≥10 partner genes that act as drivers in relatively chemotherapy resistant MLL-rearranged (MLLr) leukemias. These chimeric proteins form part of protein complexes that aberrantly upregulate transcription of the leukemogenic HOX and MEIS1 genes. Menin is a key member of the complex and localizes the complex to chromatin.
• Similarly, in NPM1 mutant (mNPM1) AML, the interaction between wild-type MLL and menin leads to a HOX and MEIS1-mediated leukemogenic transcriptional program. In preclinical models of MLLr and mNPM1 leukemias, inhibition of the interaction between MLL and menin downregulates HOX and MEIS1 transcription and reverses leukemogenesis (Uckelmann 2020; Krivstov 2019).
• SNDX-5613 (5613) is a potent, selective protein-protein interaction inhibitor of menin being evaluated in the AUGMENT-101 study, a first-in-human (FIH), Phase 1/2 study in pts with R/R acute leukemia. Here, we report the results of the completed, Phase 1 component.

Methods

• The study includes 2 parallel dose-escalation cohorts: patients not taking (Arm A) or taking (Arm B) strong CYP3A4 inhibitors.
• An early amendment restricted enrollment to MLLr or mNPM1 leukemias.
• Dose escalation used a “rolling 6” design with expansion at efficacious doses. 5613 is dosed orally q12h in continuous 28-day cycles. Dose levels evaluated in Arm A were 113 (n=1), 226 (n=6), 276 (n=10), and 339 mg (n=8), and in Arm B 113 (n=16), 163 (n=6), and 226 mg (n=7). Primary objectives of Phase 1 were to determine the safety, MTD, recommended Phase 2 dose (RP2D), and PK profile of 5613.
• Exploratory endpoints included antileukemic activity and pharmacodynamics of 5613.

Results

• As of June 29, 2021, 54 patients had received at least 1 dose of 5613; 13 patients remained on treatment. The median age was 49 years; 82% (n=44) of patients had AML; 65% (n=35) had MLLr leukemia, and 19% (n=10) had mNPM1 leukemia. Patients had a median of 3 prior therapies (range, 1-12); 57% and 44% had prior venetoclax or transplant, respectively; 59% of patients had not responded to their most recent line of therapy.
• 5613 exhibited dose-proportional PK, and exposure increased ~2-3–fold when given with a strong CYP3A4 inhibitor. Measurement of target occupancy and gene expression showed that 5613 disrupted menin binding to chromatin and decreased leukemogenic gene expression consistent with the established mechanism of action.
• The only DLTs were Grade 3 prolonged QTc; all events were clinically asymptomatic. The MTD was 276 mg q12h in Arm A and 163 mg q12h in Arm B; 2 doses in each arm met the protocol-defined criteria (safety, percentage of planned dose intensity, and pharmacokinetic exposure) for a RP2D. The frequency of Grade 3 prolonged QTc at these doses was 8% (3/38).
• No ventricular arrhythmias were reported, and no patients discontinued 5613 due to a treatment-related event. Other common (>10%) treatment-related AE (TRAE) were nausea (n=12; 22%), vomiting (n=9; 17%), differentiation syndrome (n=8; 15%), and diarrhea (n=6;11%).
• In the 45 patients with MLLr or mNPM1 leukemias, responses were seen in both Arms A and B and at multiple dose levels. The composite CR (CRc: CR+CRh+CRp+CRi/MLFS) rate was 44% (20/45 patients). Among patients with MLLr leukemia, the CRc rate was 49% (17/35 patients), and in patients with mNPM1 leukemia, the CRc rate was 30% (3/10 patients); 14/20 (70%) patients with CRc achieved MRD negativity assessed locally by flow cytometry or PCR.
• Of the 22 patients who received prior transplant, 10 (45%) achieved CRc. The CR/CRh rate was 22% (10/45) in patients with MLLr or mNPM1 leukemia. Median time to CR/CRh was 2 months (mo).
• With a median follow-up of 3.2 mo, the median duration of response (DoR) for patients achieving a CR/CRh was 5.2 mo. Responding patients were censored at the time they discontinued the study to proceed to an allogeneic stem cell transplant (n=6).
• Consistent with the proposed preclinical mechanism of menin inhibition, the 9 patients with wild-type MLL and NPM1 did not respond to 5613.

Conclusions

• In this FIH Phase 1 study, SNDX-5613 demonstrates an acceptable safety profile and promising antileukemic activity in patients with heavily pretreated R/R MLLr and mNPM1 acute leukemia. Two dose levels in each arm met the prespecified criteria for RP2D. Phase 2 expansion includes cohorts of patients with MLLr AML, MLLr ALL, and mNPM1 AML.