ziftomenib (KO-539) / Kura Oncology, University of Michigan, Kyowa Kirin - LARVOL DELTA

KOMET-001: First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=263 | Recruiting | Sponsor: Kura Oncology, Inc. | N=199 ➔ 263

Enrollment change • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

RGT-61159, A POTENT AND SELECTIVE SMALL MOLECULE MYB RNA INHIBITOR, SHOWED SIGNIFICANT ANTI-TUMOR ACTIVITY AS MONOTHERAPY OR IN COMBINATION WITH STANDARDS OF CARE IN SEVERAL LEUKEMIA DISEASE MODELS HARBORING AML MOST COMMON GENETIC LESIONS (EHA 2025) - P1 | "Significant synergistic cell killing activity was observed when RGT-61159 was combined with Flt3 inhibitors (e.g. gilteritinib and midostaurin) in MOLM-13 and MV4.11 cell lines harboring Flt3 ITD mutation, and with menin inhibitors (e.g. KO-539, revemenib) in AML cell lines with NPM1 mutation or MLL-fusion. Finally, RGT-61159 in combination with a Bcl2 inhibitor (venetoclax) resulted in synergistic cell killing activity in AML cell lines carrying NPM1 mutations or AML-1-ETO fusion protein... In summary, MYB oncogene represents a therapeutic target of relevance to AML and other hematological malignancies. RGT-61159 is a potent and selective oral small molecule inhibitor of MYB RNA and protein and an attractive therapeutic avenue to treat cancers overexpressing the oncogenic MYB protein as single agent or in combination with SoC. A phase 1 study of RGT-61159 in AML / high risk MDS is planned in addition to the ongoing phase 1 study in adults with relapsed/​refractory..."

Combination therapy • IO biomarker • Monotherapy • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation • ABL1 • BCR • FLT3 • IDH1 • NPM1

REGISTRATIONAL PHASE 3 STUDY OF ZIFTOMENIB IN COMBINATION WITH NON-INTENSIVE OR INTENSIVE CHEMOTHERAPY FOR NEWLY DIAGNOSED NPM1-M AND/OR KMT2A-R ACUTE MYELOID LEUKEMIA (AML): THE KOMET-017 TRIAL (EHA 2025) - "Current standards-of-care for NPM1-m and KMT2A-r AML include venetoclax with azacitidine (Ven/Aza; non-intensive) for unfit patients and cytarabine with daunorubicin (7+3; intensive) for fit patients. The KOMET-017 trial aims to evaluate the addition of ziftomenib to backbone standard-of-care therapies for NPM1-m and/or KMT2A-r AML; CRMRD- will also be assessed as a potential new surrogate endpoint in NPM1-m AML. KOMET-017 was designed to allow patients to enroll onto the same protocol but be treated on one of the independent registrational studies based on fitness for intensive chemotherapy. This approach is intended to be patient-centric, facilitate rapid enrollment, offer operational advantages to study sites and potentially allow for accelerated approval based on accepted surrogates for meaningful clinical benefit."

Combination therapy • P3 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

OUTCOMES OF RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA AFTER MENIN INHIBITION (EHA 2025) - "Prior to MENINi, 84% (n=43) of patients had received intensive chemotherapy (IC) and 73% (n=37) had received venetoclax (VEN)-based therapy...The most used MENINi was revumenib (n=40, 78%), followed by ziftomenib (n=9, 18%)...Of these 4 responders, 3 received AZA (azacitidine)/VEN, 1 received FLAG-IDA/VEN, and all 4 were VEN-naïve...No patients with FLT3-ITD after MENINi responded to further therapy, including 8 treated with gilteritinib (GILT), despite 4 of them being GILT-naïve... MENINi are promising in AML, but outcomes after failure are poor. Responses to post-MENINi therapy can be seen with VEN-based regimens in VEN-naïve patients. Studies focused on sequencing as well as preventing and overcoming MENINi resistance are needed."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • KMT2A • MEN1 • NPM1 • NUP98 • WT1

ZIFTOMENIB IN RELAPSED/REFRACTORY NPM1-MUTANT ACUTE MYELOID LEUKEMIA: PHASE 1B/2 CLINICAL ACTIVITY AND SAFETY RESULTS FROM THE PIVOTAL KOMET-001 STUDY (EHA 2025) - P1/2 | "In the pivotal KOMET-001 study, the phase 2 primary endpoint was met. Ziftomenib achieved deep and durable responses in R/R NPM1-m AML, with comparable clinical activity regardless of prior venetoclax exposure. Ziftomenib was well tolerated with limited myelosuppression and only 3% ziftomenib-related discontinuations."

Clinical • P1/2 data • Acute Myelogenous Leukemia • Anemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Thrombocytopenia • KMT2A • NPM1

COMBINING MENIN INHIBITION (ZIFTOMENIB) WITH VENETOCLAX ENHANCES ANTI-LEUKEMIC ACTIVITY IN PRECLINICAL MODELS OF HUMAN KMT2AR ACUTE LYMPHOBLASTIC LEUKEMIA (EHA 2025) - "Addition of Ven to Zifto improved the anti-leukemic activity of menin inhibition in preclinical human B-ALL models via induction of apoptosis, decreased cell cycle and proliferation, and lymphoid differentiation. Therapy with Zifto+Ven also significantly reduced leukemic disease burden and delayed progression in a systemic human in vivo leukemia xenograft mouse model. These studies support the development of future clinical trials exploring menin inhibition combined with Venetoclax for relapsed/refractory KMT2Ar ALL."

IO biomarker • Preclinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CD20 • KMT2A

ZIFTOMENIB COMBINED WITH INTENSIVE INDUCTION CHEMOTHERAPY (7+3) IN NEWLY DIAGNOSED NPM1-M OR KMT2A-R ACUTE MYELOID LEUKEMIA (AML): UPDATED PHASE 1A/B RESULTS FROM KOMET-007 (EHA 2025) - P1 | "KOMET-007 (NCT05735184) is an ongoing dose-escalation (ph1a) and expansion (ph1b) study of ziftomenib in combination with standard chemotherapies in NPM1-m or KMT2A-r AML.Aims: Here we present updated safety and clinical activity in all newly diagnosed AML patients (pts) treated at the recommended phase 2 dose (RP2D) of ziftomenib 600 mg once-daily (QD) in combination with standard doses of cytarabine and daunorubicin (7+3) across ph1a/b of KOMET-007.Adults (≥18y) with newly diagnosed NPM1-m or KMT2A-r AML received the ziftomenib RP2D of 600 mg QD in combination with 7+3 induction, followed by consolidation with cytarabine and/or hematopoietic stem cell transplantation. In the ongoing KOMET-007 study, ziftomenib RP2D of 600 mg QD combined with 7+3 was well tolerated and continued to demonstrate robust and evolving clinical activity in newly diagnosed AML: CRc of 94% in NPM1-m and 83% in KMT2A-r pts. No DS events were reported, with low rates of ziftomenib-related..."

P1 data • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • KMT2A • NPM1

Menin inhibitors from monotherapies to combination therapies: clinical trial updates from 2024 ASH annual meeting. (PubMed, J Hematol Oncol) - "Following the promising outcomes of the two pioneering menin inhibitors, revumenib and ziftomenib, other menin inhibitors, including bleximenib, enzomenib, BN-104 and HMPL-506 are currently under investigation in clinical trials. Several trials presented their initial outcomes at the 2024 ASH Annual Meeting. This review highlights the key outcomes of these pivotal clinical trials."

Journal • Review • Hematological Malignancies • Leukemia • Oncology • KMT2A • MEIS1 • NPM1 • NUP98

Kura Oncology and Kyowa Kirin Report Positive Updated Combination Data for Ziftomenib in Newly Diagnosed AML at 2025 European Hematology Association Congress (GlobeNewswire) - P1a/1b | N=212 | KOMET-007 (NCT05735184) | Sponsor: Kura Oncology, Inc. | Kura Oncology...provided positive updated clinical data from KOMET-007...in patients with newly diagnosed NPM1-mutant (NPM1-m) and KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML)....Median follow-up times for the two populations were 24.9 weeks (range 4.3-47.1) in NPM1-m patients and 15.7 weeks (range 1.1-40.3) in KMT2A-r patients. Among response-evaluable NPM1-m patients, neither a median duration of CR nor a median overall survival (OS) had been reached. Among response-evaluable KMT2A-r patients, a median duration of CR was determined to be 25.6 weeks (95% CI, range 8.3-NE), and a median OS had not been reached. Notably, 96% (47/49) of NPM1-m patients and 88% (29/33) of KMT2A-r patients remained alive and on study....KOMET-017-IC (intensive chemotherapy) and NIC (non-intensive chemotherapy) randomized phase 3 studies (NCT07007312) expected to start in 2H 2025."

P1 data • Trial status • Acute Myelogenous Leukemia

Kura Oncology and Kyowa Kirin Announce FDA Acceptance and Priority Review of New Drug Application for Ziftomenib in Adults with Relapsed or Refractory NPM1-Mutant AML (GlobeNewswire) - "Kura Oncology...and Kyowa Kirin...announced the U.S. Food and Drug Administration (FDA) has accepted Kura’s New Drug Application (NDA) seeking full approval for ziftomenib as a treatment for adult patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) with a nucleophosmin 1 (NPM1) mutation. The application has been granted Priority Review and assigned a Prescription Drug User Fee Act (PDUFA) target action date of November 30, 2025....The NDA is based on results from the Phase 2 KOMET-001 registrational trial in R/R NPM1-mutant (NPM1-m) AML (NCT #04067336). The KOMET-001 trial achieved its primary endpoint of complete remission (CR) plus CR with partial hematological recovery (CRh) and the primary endpoint was statistically significant."

Evidence highlight • FDA filing • PDUFA • Priority review • Acute Myelogenous Leukemia • Oncology • NPM1

Studies to Assess Ziftomenib in Combination With Ven+Aza or 7+3 in Patients With Untreated NPM1-m or KMT2A-r AML (clinicaltrials.gov) - P3 | N=1300 | Not yet recruiting | Sponsor: Kura Oncology, Inc.

New P3 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • NPM1

Ziftomenib in relapsed/refractory (R/R) NPM1-mutant acute myeloid leukemia (AML): Phase 1b/2 clinical activity and safety results from the pivotal KOMET-001 study. (ASCO 2025) - P1/2 | "Median age was 69 yrs (range 22–86), 56% female, 83% ECOG PS 0–1, median of 2 prior therapies (range 1–7), including 60% prior venetoclax (VEN) and 23% prior transplant... In the pivotal KOMET-001, the phase 2 primary endpoint was met: Ziftomenib achieved deep and durable responses in R/R NPM1-m AML, regardless of prior VEN. Ziftomenib was well tolerated with limited myelosuppression and only 3% ziftomenib-related discontinuations. Taken together, these data support the potential use of ziftomenib monotherapy as a new treatment option for R/R NPM1-m AML."

Clinical • P1/2 data • Acute Myelogenous Leukemia • Anemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Thrombocytopenia • KMT2A • NPM1

Phase 1a/1b study of the safety, pharmacokinetics, and antitumor activity of ziftomenib in combination with imatinib in patients with advanced gastrointestinal stromal tumors (GIST) after imatinib failure. (ASCO 2025) - P1 | "All adverse events will be recorded, monitored, and graded based on CTCAE v5.0. The trial is open and actively recruiting with sites in the United States."

Clinical • Combination therapy • Metastases • P1 data • PK/PD data • Stroma • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • KIT • KMT2A

Kura Oncology and Kyowa Kirin Report Positive Pivotal Ziftomenib Monotherapy Data at 2025 ASCO Annual Meeting (GlobeNewswire) - P1b/2 | N=199 | KOMET-001 (NCT04067336) | Sponsor: Kura Oncology, Inc. | "A complete remission (CR) plus CR with partial hematological recovery (CRh) rate of 23% (21/92) was observed among patients with R/R NPM1-m AML in the Phase 2 portion of the KOMET-001 trial. Among those 21 patients who achieved CR/CRh, 13 had a CR and 8 had a CRh. The median duration of CR/CRh responses was 3.7 months (95% CI: 1.9, not estimable (NE)) and the restricted mean duration of response was 4.3 months (95% CI: 3.1, 5.6) at the time of the data cutoff. MRD status was assessed in 19 of 21 patients who achieved CR/CRh, and 63% (12/19) of these patients were MRD-negative. Comparable CR/CRh rates were observed across pre-specified subgroups, regardless of prior HSCT, prior venetoclax or FLT3/IDH co-mutations."

P2 data • Acute Myelogenous Leukemia

Study Featured at ASCO 2025 Highlights Potential New Treatment for Aggressive Form of Acute Myeloid Leukemia (PRWeb) - P1b/2 | N=199 | KOMET-001 (NCT04067336) | Sponsor: Kura Oncology, Inc. | "By late 2024, the phase 2 KOMET-001 trial had enrolled 112 patients in North America and Europe - all with relapsed/refractory NPM1-mutated AML. Patients received ziftomenib 600 mg orally once a day as monotherapy, without additional drugs. In phase 2, at a median follow-up of 4.2 months, 23% (21 of 92 patients) achieved complete response (CR) or complete response with partial hematological recovery (CRh), meaning their blood cell counts had partially returned to normal after treatment. Of the 23% who were tested, 67% (10 of 15 patients) had no detectable disease by measurable residual disease testing. Ziftomenib was generally well tolerated, with only 3% of patients (3 of 112) in the combined phase 1B/2 population discontinuing treatment due to treatment-related adverse side effects."

P2 data • Acute Myelogenous Leukemia

Menin Inhibitors in KMT2A-Rearranged and NPM1-Mutated Acute Leukemia: A Scoping Review of Safety and Efficacy. (PubMed, Crit Rev Oncol Hematol) - "Menin inhibitors demonstrate promising clinical activity in molecularly defined leukemias, with Revumenib establishing proof-of-concept for this therapeutic approach. However, challenges remain, including resistance development, optimal timing of therapy initiation, and determination of effective combination strategies. Larger randomized trials with extended follow-up are needed to establish long-term efficacy and safety profiles. The rapid clinical development of multiple agents in this class suggests an expanding role for Menin inhibitors in leukemia treatment paradigms."

Journal • Review • Hematological Malignancies • Leukemia • Oncology • KMT2A • MEN1 • NPM1

Kura Oncology and Kyowa Kirin Announce Pivotal Monotherapy Data for Ziftomenib in Oral Presentation at the 2025 ASCO Annual Meeting (GlobeNewswire) - "Kura Oncology...and Kyowa Kirin...announced that an abstract highlighting the full data analyses from the KOMET-001 registration-directed trial of ziftomenib, a once-daily, oral investigational menin inhibitor, has been accepted for oral presentation at the upcoming 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, to be held in Chicago, IL from May 30 - June 3, 2025.....In addition to the oral presentation, a trial-in-progress abstract for the KOMET-015 trial has been accepted for poster presentation on May 31, 2025....Updated data from the published abstract for KOMET-001 will be disclosed during the oral presentation."

P1/2 data • Trial status • Acute Myelogenous Leukemia • Gastrointestinal Stromal Tumor

Insights into KMT2A rearrangements in acute myeloid leukemia: from molecular characteristics to targeted therapies. (PubMed, Biomark Res) - "Menin inhibitors (e.g., Revumenib, Ziftomenib) disrupt the Menin-KMT2A interaction, suppressing HOXA/MEIS1 and promoting differentiation. DOT1L inhibitors (e.g., Pinometostat) show promise in combination therapies, while novel approaches like WDR5 inhibitors and PROTAC-mediated degradation are expanding treatment options. Despite progress, challenges remain, including optimizing minimal residual disease monitoring, overcoming resistance, and validating biomarkers. This review emphasizes the imperative to translate molecular insights into personalized therapeutic regimens, offering renewed hope for patients afflicted by this historically refractory malignancy."

Journal • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • DOT1L • KMT2A • MEIS1 • WDR5

Kura Oncology and Kyowa Kirin Announce Combination Data for Ziftomenib in Oral Presentation at the 2025 European Hematology Association (EHA) Congress (GlobeNewswire) - "Kura Oncology, Inc...today announced that an abstract highlighting clinical data from the KOMET-007 combination trial of ziftomenib, a once-daily, oral investigational menin inhibitor, has been accepted for presentation at the upcoming 2025 European Hematology Association (EHA) Congress, to be held in Milan, Italy, from June 12-15, 2025....In addition to the oral presentation, two abstracts for the KOMET-001 and KOMET-017 trials have been accepted for an encore presentation and publication, respectively." "

Clinical data • Acute Myelogenous Leukemia

Kura Oncology Reports First Quarter 2025 Financial Results (GlobeNewswire) - "Forecasted Milestones: (i) Present data from the KOMET-001 Phase 1b/2 registration-directed trial in R/R NPM1-m AML at ASCO and EHA in the second quarter of 2025; (ii) Present preliminary clinical data from the KOMET-007 Phase 1b expansion cohort evaluating ziftomenib with intensive chemotherapy (7+3) in the frontline setting at EHA in the second quarter of 2025; (iii) Present preliminary clinical data from the KOMET-007 Phase 1b expansion cohort evaluating ziftomenib with venetoclax and azacitidine in the frontline setting at a medical meeting in the second half of 2025; (iv) Initiate two independent Phase 3 registration-enabling trials in 1L intensive (KOMET-017-IC) and non-intensive (KOMET-017-NIC) AML in the second half of 2025."

Clinical data • New P3 trial • Acute Myelogenous Leukemia

RGT-61159, best-in-class oral small molecule inhibitor of MYB via selective RNASplicing alteration, synergistic anti-tumor aActivity when combined with standards of care in leukemia disease models harboring AML common genetic lesions and with NOTCH inhibitors in ACC disease models (AACR 2025) - P1 | "The data revealed synergistic cell killing activity when RGT-61159 was combined with Flt3 inhibitors (e.g. gilteritinib and midostaurin) in MOLM-13 and MV4.11 cell lines harboring Flt3 IDT mutation, and with menin inhibitors (e.g. KO-539, revemenib) in AML cell lines with NPM1 mutant) or MLL-fusion. Finally, RGT-61159 combination with a Bcl2 inhibitor (venetoclax) resulted in synergistic cell killing activity in AML cell lines carrying NPM1 mutations or AML-1-ETO fusion protein. These studies provide compelling supportive evidence for combining RGT-61159 with standards-of-care for AML treatment in the relevant population of patients with AML. ."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • NPM1

Kura Oncology Announces First Patients Dosed in Phase 1 Combination Trial of Ziftomenib for the Treatment of Advanced GIST (GlobeNewswire) - "Kura Oncology, Inc...today announced that the first patients have been dosed in KOMET-015, a Phase 1 clinical trial of ziftomenib, the Company’s potent and selective, oral investigational menin inhibitor, in patients with advanced gastrointestinal stromal tumors (GIST) after imatinib failure."

Trial status • Gastrointestinal Stromal Tumor

KMT2A rearranged acute myeloid leukemia is vulnerable to the combinatorial inhibition of menin and MYC protein degradation (AACR 2025) - "This interaction has been targeted by menin inhibitors revunemib and ziftomenib with promising results in clinical trials (Aldoss & Issa, 2023; Erba, 2022), and revumenib is now FDA-approved...We have investigated GT19715, the first-in-class MYC/GSPT1 degrader in MYC-driven hematological malignancies (Nishida, ASH 2022, 2023, 2024)... Combinatorial approach of menin inhibition and MYC degradation results in a profound synergistic reduction of KMT2Ar AML cells in vitro and in vivo, validating the underlying premise. Further mechanistic studies and efficacy in PDX models are ongoing."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • GSPT1 • KMT2A • MYC • TP53

RCZY-711, a novel, highly potent, and orally bioavailable menin-MLL inhibitor with superior efficacy in preclinical acute leukemia models (AACR 2025) - "The FDA-approved menin inhibitor SNDX-5613 treats relapsed/refractory acute leukemia with MLL translocations, while ongoing trials explore its use in KRAS-mutant solid tumors and Wnt-driven cancers. Another menin inhibitor, KO-539, is being tested in advanced gastrointestinal stromal tumors...The observed superior in vivo efficacy may be attributed to its high cellular potency and improved half-life (mouse: T1/2 = 2.0 h). In conclusion, RCZY-711 is a novel, highly potent and orally bioavailable menin-MLL inhibitor with best-in-class clinical potential for treating MLL-rearranged and NPM1-mutant acute leukemias."

Preclinical • Acute Myelogenous Leukemia • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Hematological Malignancies • Leukemia • Oncology • Sarcoma • Solid Tumor • KMT2A • KRAS • MEIS1 • MEN1 • NPM1

Lintuzumab-Ac225 has potent mutation agnostic antileukemic activity in preclinical models of AML (AACR 2025) - "In clinical trials, lintuzumab-Ac225 had positive responses when combined with CLAG-M chemotherapy in relapsed/refractory AML patients, including those with high-risk features like venetoclax resistance and TP53 mutations...FLT3 inhibitors (gilteritinib, quizartinib), KMT2A inhibitors (revumenib, ziftomenib) and azacitidine were evaluated as single agents and in combination with Lintuzumab-Ac225... Lintuzumab-Ac225 shows broad anti-leukemic activity in AML cell lines, in a mutation (FLT3, KMT2A, NPM1, TP53) agnostic manner. It improves AML control in high-risk cases and enhances response durability when combined with standard of care treatments. These findings support its potential as a backbone therapy for relapsed/refractory AML, warranting further clinical evaluation."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33 • CDKN1A • FLT3 • KMT2A • NPM1 • TP53