Breakthrough Clinical Results
Kura Oncology and Kyowa Kirin announced positive pivotal data for ziftomenib, an oral menin inhibitor, in patients with relapsed/refractory (R/R) NPM1-mutant acute myeloid leukemia (AML). The data, from the KOMET-001 trial (NCT #04067336), will be presented orally at the 2025 ASCO Annual Meeting. The trial met its primary endpoint of complete remission (CR) plus CR with partial hematological recovery (CRh), demonstrating statistically significant results. Ziftomenib showed a favorable safety and tolerability profile with limited myelosuppression. A New Drug Application has already been submitted for ziftomenib for the treatment of adult patients with R/R NPM1-m AML. Kura Oncology will host a virtual investor event to discuss the results.
Key Highlights
- Positive topline results from the KOMET-001 trial met the primary endpoint of CR+CRh in R/R NPM1-mutant AML.
- Ziftomenib demonstrated a favorable safety and tolerability profile with limited myelosuppression.
- Data will be presented orally at the 2025 ASCO Annual Meeting.
- NDA for ziftomenib has been submitted for R/R NPM1-m AML.
Incidence and Prevalence
Global Estimates of Acute Myeloid Leukemia Incidence and Prevalence
Global Incidence Trends
Acute myeloid leukemia (AML) has shown a significant increase in global incidence over recent decades. AML accounted for 18.0% of total leukemia cases worldwide in 1990, which increased to 23.1% by 2017.
The age-standardized incidence rate (ASIR) of AML has risen from 1.35 per 100,000 in 1990 to 1.54 per 100,000 in 2017. This represents an estimated average percentage change (EAPC) of 0.56 (95% CI 0.49, 0.62), confirming a statistically significant upward trend in AML incidence globally.
This increasing trend is geographically widespread, with 127 countries or territories experiencing a significant increase in the ASIR of AML during this period.
Regional Variations
The incidence of AML shows notable regional differences:
- In European populations, the age-adjusted incidence rate for AML was 2.96 per 100,000 (based on 2000-2002 data)
- In Hong Kong (2014-2016), the incidence rate for overall AML was 2.23 cases per 100,000
- Asia accounts for 48.6% of all leukemia cases globally
- India specifically reports approximately 10.2% of all leukemia cases worldwide
Proportion of Leukemia Cases
The proportion of acute leukemia cases classified as AML varies significantly by region:
- In Oman, 34% of acute leukemia cases were classified as AML
- At an Egyptian institution (2009-2010), a much higher 68.9% of acute leukemia cases were classified as AML
These statistics reflect the growing global burden of AML, with evidence of increasing incidence rates across numerous countries and significant regional variations in both incidence and the proportion of leukemia cases attributed to AML.
Key Unmet Needs and Target Populations for Acute Myeloid Leukemia
Key Unmet Needs
Treatment Challenges
- Elderly and unfit patients cannot receive intensive therapy due to unacceptable risk of treatment-related morbidity and mortality
- These patients require disease-stabilizing therapy approaches, such as all-trans retinoic acid (ATRA) combined with histone deacetylase inhibitor valproic acid
- Patients with high blast counts (>30% blasts in bone marrow) experience significantly lower benefits from azacitidine
- Cost-utility analysis showed azacitidine is unlikely to be cost-effective in this population, with an incremental cost-effectiveness ratio of $Can160,438 (2018)
Immunotherapy Challenges
- Unlike solid tumors, immune checkpoint inhibitors have shown underwhelming results in AML
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Major challenges include:
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Validation of predictive biomarkers (genetic, molecular, and immunophenotypic)
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Optimization of clinical trial design
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Identification of novel synergistic combination therapies
Factors Limiting Immunotherapy Success
- Relatively low mutational burden of AML blasts
- Difficulty in defining AML-specific antigens not expressed on hematopoietic progenitor cells
- Few neo-antigens compared with solid cancers
Target Populations
Specific Patient Groups
- Elderly and unfit patients requiring alternative treatment approaches
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CD34+ AML patients associated with drug resistance and poor outcomes
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Bortezomib showed potential in treating these patients, with significantly more activity than doxorubicin in CD34+ cells
- Patients with high blast counts (>30% blasts in bone marrow)
- Patients with relapsed/refractory AML
- Adult and pediatric patients with de novo AML
Genomic and Molecular Profiles
- Patients with different cytogenetic and molecular profiles (NPM1 mutated, FLT3-ITD mutated)
- Patients with specific immunological markers (CD81, CD123, CD34+CD123+, CD33+CD123+)
Demographic Considerations
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Underrepresented populations in clinical trials:
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Blacks, Native Americans, and Hispanics
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Females (noted to be under-represented in AML clinical trials at 44.7% vs 60.5% in general population)
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Patients from diverse geographic distributions
Emerging Approaches
- Studies of CAR-T, CAR-NK, adaptor CAR-T, and allogeneic NK-cells are progressing
- Combining selective targeted epigenetic drugs with immunotherapy shows promise
- Anti-CD47 antibody showed substantial efficacy against AML when combined with azacitidine
- Immune-related long non-coding RNA (lncRNA) prognostic risk models show potential for predicting AML survival
Study Design Parameters
Study Design Parameters and Endpoints in Key Trials for Acute Myeloid Leukemia
Study Design Parameters
Several key trials have examined different aspects of Acute Myeloid Leukemia (AML) treatment using various study designs:
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A micafungin study for febrile neutropenic patients used an observational design where the treatment was administered for sustained fever following empirical antibiotic therapy. The study population included 47 patients with various conditions including acute myeloid leukemia.
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A TLR4 pathway study employed both laboratory and clinical approaches, examining mRNA expression of TLR4, MyD88, RelB, and NF-кB using qRT-PCR in bone-marrow samples. The study population consisted of 40 AML patients categorized by prognosis, cell type, age, and drug response, along with NB4, U937, and KG-1 cell lines.
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A gene expression profiling study based on landmark Golub et al. data examined whether expression profiles at diagnosis could predict eventual response to chemotherapy.
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An FLT3 inhibitor study utilized laboratory cellular assays with Ba/F3 cell lines expressing oncogenic FLT3 mutations to compare treatments.
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An imatinib comparative study compared original imatinib (OI) versus generic imatinib (GI) in 90 patients divided into 2 groups.
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A retrospective study of elderly AML patients used the Surveillance, Epidemiology, and End Results cancer registry with linked Medicare claims, analyzing 4,058 patients aged 65+ years diagnosed with AML between 1997-2007.
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The AZA-001 trial evaluated azacitidine in older patients with WHO-defined AML with low marrow blasts (20%-30%).
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The Cancer and Leukemia Group B 9221 was a large phase III clinical trial that provided main clinical evidence for azacitidine in AML patients.
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A Vietnamese study of 50 newly diagnosed AML patients (excluding acute promyelocytic leukemia) administered induction therapy followed by three cycles of consolidation therapy.
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A functional precision medicine study included 252 samples from 186 patients with AML, integrating clinical, molecular, and functional data for application in clinical treatment decisions.
Study Endpoints
The trials utilized various endpoints to assess efficacy and safety:
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The micafungin study measured overall success rate and side effects, reporting a 61.7% overall success rate, with grade 3/4 liver enzyme elevations in 6.4% and hyperbilirubinemia in 21%.
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The TLR4 pathway study assessed cell proliferation and cell cycle analysis after treatment with TAK-242 and arsenic trioxide.
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The gene expression profiling study focused on predicting eventual response to chemotherapy based on diagnostic gene expression profiles.
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The FLT3 inhibitor study measured cell proliferation, used Western blotting, and assessed cell death through propidium-iodide staining and flow cytometry.
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The imatinib study tracked BCR-ABL1 transcript levels at 3 and 6 months, complete cytogenetic response, major molecular response, event-free survival, and measurements of early molecular response and optimal response.
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The retrospective study of elderly AML patients examined treatment patterns, survival time, healthcare utilization and costs, finding that 43% received chemotherapy with median survival of 7.0 months versus 1.5 months for the 57% receiving supportive care only.
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The AZA-001 trial measured median overall survival compared to conventional care regimens.
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The Vietnamese study assessed treatment efficacy on day 28 after the first chemotherapy course and on day 28 after the fourth chemotherapy course.
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The functional precision medicine study evaluated objective response rate for individually tailored therapies, achieving 59% objective response rate, including 13 complete responses and bridging five patients to allogeneic hematopoietic stem cell transplantation.
Drug used in other indications
The context does not contain any information about Ziftomenib clinical trials for Acute myeloid leukemia or any other indications. Similarly, there is no information provided about intervention models for Ziftomenib trials.