Activity Demonstrated in R/R AML With Menin Inhibitor in First-in-Human Trial


The oral, selective menin inhibtor KO-539 showed activity in preliminary findings of the ongoing first-in-human KOMET-001 trial in patients with relapsed/refractory acute myeloid leukemia.

Eunice S. Wang, MD

The oral, selective menin inhibitor KO-539 showed activity in preliminary findings of the ongoing first-in-human KOMET-001 trial in patients with relapsed/refractory acute myeloid leukemia (AML), according to a presentation from Eunice S. Wang, MD, at the 2020 American Society of Hematology Annual Meeting.1

Single-agent KO-539 therapy showed activity in 6 of 8 evaluable patients across dose levels, including 3 treated in a 200-mg cohort, and across varied genomic subgroups, including 2 participants who achieved a complete remission (CR).

“KO-359 is a once-daily, oral investigative drug candidate targeting the KMT2A(MLL)-menin protein-protein interaction,” said Wang, who is chief of Leukemia Service, medical director of Infusion Services, at Roswell Park Comprehensive Cancer Center, and an associate professor in the Department of Medicine at Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo. “The KMT2A gene plays an essential role in regulating gene expression of the HOXA9 and MEIS1 promoters. Rearrangements of the KMT2A gene have been identified in 5% to 10% of AML cases and associated with poor prognosis.”

The overall survival rate for patients with KMT2A(MLL) translocation is approximately 35%. Further, patients with NPM1-mutant AML have an overall survival rate of less than 50% when those mutations occur along with FLT3-ITD mutations.2 These 2 subgroups historically have represented an unmet need in the AML treatment landscape.

“Treatment of patients with KMT2A-rearranged or NPM1-mutant AML cells with KO-539 is hypothesized to reduce transcription of HOXA9 and MEIS1 promoters and result in terminal differentiation of AML blasts,” Wang said.

Investigators enrolled 12 patients to 1 of 4 dosing cohorts in the phase 1/2a KOMET-001 trial (NCT04067336). At data cutoff on November 2, 2020, 1 patient each were enrolled to the 50- and 100-mg cohorts, 6 in the 200-mg cohort, and 4 in the 400-mg cohort. “[The 50-mg and 100-mg cohorts] were followed by an expansion to 6 patients at 200 mg daily to better characterize the drug PK [pharmacokinetics] and exposure of KO-539,” Wang explained.

A dose of 600 mg is predicted as the efficacious dose by investigators; however, dose escalation will continue until dose-limiting toxicities are observed.1

The median age was 67 years (range, 33-80) and patients had received a median of 3 prior lines of therapy (range, 2-7). Of those treated, 6 remain on treatment, 1 patient is in follow-up, and 5 patients are off study. Of 6 patients who discontinued study treatment, 4 had disease progression, 1 had symptomatic deterioration, and 1 withdrew consent. Among 5 patients who stopped participating in the study, the reasons included death in 2 patients and physician decision to withdraw 2 patients who subsequently died.

In preliminary efficacy data, a marked decrease in hydroxyurea requirements was observed in the single patient with KMT2A-rearranged AML treated at the 50-mg dose level. In the 100-mg cohort, the single enrolled patient with SETD2/RUNX1-mutated AML achieved a CR. “Of note, [this] patient receiving 100 mg per day was dose escalated to 200 mg per day on cycle 7 and achieved a best response of CR with MRD [measurable residual disease] positivity at 100 mg. The patient had clinical benefit for more than 6 months prior to disease progression.”

Of the 3 patients enrolled to the 200-mg cohort, 1 heavily pretreated patient with a mutational profile that included NPM1DNMT3A, and KMT2D aberrations achieved a CR. “[This patient] attained a CR with no measurable residual disease and remain on therapy after 3 cycles,” Wang noted. This patient had received 7 lines of prior therapy.

The remaining 2 patients in the 200-mg cohort harbored U2AF1/TET2/TP53/DNMT3A/PTPN11 and NPM1/FLT3-ITD/TET2/CUX1 mutations, respectively. The observed clinical activity for these patients was stable disease and morphological leukemia-free state, respectively.

The final patient, who was treated in the 400-mg cohort, demonstrated decreased peripheral blasts and had a mutational profile that included RUNX1SRSF2ASXL1TET2STAG2BCOR, and PTPN11.

Wang highlighted that activity was seen across patients independent of concomitant CYP3A4 inhibitor therapy, which include antifungal medicines.

Overall, Wang said, KO-539 was well tolerated with a manageable safety profile. There have been no drug discontinuations due to treatment-related adverse effects (AEs). Grade 3 or higher AEs including pancreatitis, increased lipase, decreased neutrophil count, tumor lysis syndrome, and deep vein thrombosis were each reported in 1 patient (8.3%). Grade 1/2 AEs included nausea in 3 patients (25%), rash in 2 (16.7%), and diarrhea in 2 (16.7%).

Further, there has been no evidence of QT prolongation or other clinically significant electrocardiogram changes, Wang said.

KOMET-001 is continuing to enroll patients for the phase 1 dose escalation portion of the study with plans for a phase 2 expansion stage. There are 2 genomic cohorts planned for the expansion state: patients with NPM1-mutant AML, and those with KMT2A(MLL)-rearranged AML.

In 2019, the FDA granted KO-539, developed by Kura Oncology, an orphan drug designation for the treatment of patients with AML.3


1. Wang ES, Altman JK, Pettit KM, et al. Preliminary data on a phase 1/2A first in human study of the menin-KMT2A (MLL) inhibitor KO-539 in patients with relapsed or refractory acute myeloid leukemia. Presented at: 2020 American Society of Hematology Annual Meeting and Exposition. December 5-8, 2020; Virtual. Abstract 115.

2. Klossowski S, Miao H, Kempinska K, et al. Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia. J Clin Invest. 2020;130(2):981-997. doi:10.1172/JCI129126

3. Kura Oncology’s menin-MLL inhibitor KO-539 receives orphan drug designation from FDA for Treatment of acute myeloid leukemia. News release. Kura Oncology. July 24, 2019. Accessed December 4, 2020.

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