On December 9, 2024 Kura Oncology, Inc. (Nasdaq: KURA, "Kura") and Kyowa Kirin Co., Ltd. (TSE: 4151, "Kyowa Kirin") reported encouraging clinical data from KOMET-007, a Phase 1 dose-escalation trial of ziftomenib, a highly selective oral investigational menin inhibitor, in combination with standards of care, including cytarabine/daunorubicin (7+3) and venetoclax/azacitidine (ven/aza), in patients with NPM1-mutant (NPM1-m) and KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) (Press release, Kyowa Hakko Kirin, DEC 9, 2024, View Source [SID1234648906]).
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These data were presented at the 2024 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. An oral presentation highlighting ziftomenib combined with 7+3 in newly diagnosed (1L) NPM1-m and KMT2A-r adverse riski AML, and a poster featuring ziftomenib in combination with ven/aza in relapsed/refractory (R/R) NPM1-m and KMT2A-r AML are available in the Posters and Presentations section on Kura’s website.
Ziftomenib was generally well tolerated in combination at all dose levels evaluated across all cohorts in the Phase 1a dose-escalation portion of the study. No dose-limiting toxicities, evidence of ziftomenib-associated QTc prolongation, drug-drug interactions or additive myelosuppression were observed. In the 7+3 combination cohorts, on-target differentiation syndrome (DS) occurred in 2% (1/51) of patients. Grade ≥3 treatment emergent adverse events occurring in ≥20% were febrile neutropenia platelet count decreased, anemia and neutropenia count decrease and white blood cell count decreased. In the ven/aza combination cohorts, on-target DS occurred in 8% (4/53) of patients. Grade ≥3 treatment emergent adverse events occurring in ≥20% were platelet count decreased, anemia and febrile neutropenia. All instances of DS were manageable, and no patients discontinued participation due to DS. The Phase 1b expansion portion of KOMET-007 is now enrolling at 600 mg in all cohorts, including patients with 1L NPM1-m or KMT2A-r AML in combination with ven/aza.
Among the response-evaluable patients enrolled in the 7+3 combination cohort for patients with 1L NPM1-m or KMT2A-r adverse riski AML, 91% (42/46) achieved a complete remission (CR) (100% for NPM1-m, 83% for KMT2A-r patients). MRD negativity was 76% in NPM1-m and 75% in KMT2A-r patients. All NPM1-m patients (24/24) and 96% (26/27) of KMT2A-r patients remained alive as of the data cutoff on October 1, 2024, with a median follow-up of 31 and 19 weeks, respectively.
A total of 54 patients were enrolled in the combination cohort with ven/aza in R/R NPM1-m or KMT2A-r AML. The NPM1-m population achieved an overall response rate (ORR) of 68% (15/22) and a composite complete remission (CRc) rate of 50% (11/22). In NPM1-m patients with previous ven exposure, ORR was 50% (7/14) and CRc was 36% (5/14). In KMT2A-r patients, 30% of patients responded, including those with prior ven exposure.
"The findings presented at ASH (Free ASH Whitepaper) underscore the potential of ziftomenib in combination with standards of care as an early intervention in the frontline setting of AML and could offer a meaningful opportunity to improve patient outcomes," said Amer Zeidan, MBBS, MHS, chief of the Division of Hematologic Malignancies, director of Hematology Early Therapeutics Research at Yale Cancer Center, and lead investigator of the KOMET-007 trial. "The high rates of complete remission and MRD negativity across the 7+3 cohorts are particularly encouraging. The rapid enrollment in the Phase 1a portion of this study underscores the urgency and enthusiasm for further evaluating this combination approach."
Kura and Kyowa Kirin recently announced plans for KOMET-017, a global, pivotal Phase 3 study evaluating ziftomenib in combination with standards of care for adults with newly diagnosed KMT2A-r or NPM1-m AML. The trial includes two independently powered, randomized, double-blind, placebo-controlled studies: a non-intensive therapy arm testing ziftomenib with ven/aza, and an intensive therapy arm testing ziftomenib with 7+3. The positive results from KOMET-007 reported at ASH (Free ASH Whitepaper) reinforce Kura’s and Kyowa Kirin’s commitment to evaluating ziftomenib for patients across the continuum of frontline treatment options. The KOMET-017 study is expected to initiate in mid-2025.
"Starting patients on therapy early is essential to improving outcomes in AML," said Mollie Leoni, M.D., Executive Vice President, Clinical Development at Kura Oncology. "The updated KOMET-007 data underscore the combination potential of ziftomenib in the frontline setting, strengthening our confidence in its ability to provide a valuable treatment option for a significant portion of the AML population. Together, the KOMET-007 Phase 1b trial and the KOMET-017 pivotal Phase 3 study will allow us to further explore this approach and the potential to transform care if approved for AML patients worldwide."
"More than half of AML patients with an NPM1 mutation will relapse with poor survival outcomesii, making it a significant area of unmet medical need in the frontline setting," said Takeyoshi Yamashita, Ph.D., Senior Managing Executive Officer and Chief Medical Officer of Kyowa Kirin. "The data observed to date represent the potential of ziftomenib to help address the treatment gap and improve upon current standards of care. Leveraging our hemato-oncology expertise and commitment to patients, we are committed to rapidly advancing the clinical development of ziftomenib."
Virtual Investor Event
Kura will host a webcast and conference call featuring Kura Oncology management and Key Opinion Leaders Amir T. Fathi, MD, Associate Professor of Medicine at Harvard Medical School and Director of the Leukemia Program at Massachusetts General Cancer Center, and Amer Zeidan, MBBS, MHS, interim chief of the Division of Hematologic Malignancies, Director of Hematology Early Therapeutics Research at Yale Cancer Center. The live call may be accessed by dialing (800) 715-9871 for domestic callers and (646) 307-1963 for international callers and entering the conference ID: 4326549. A live webcast will be available here and in the Investors section of Kura’s website, with an archived replay available shortly after the event.
About Ziftomenib
Ziftomenib is a selective and oral menin inhibitor currently in development for the treatment of genetically defined AML patients with high unmet need. In April 2024, ziftomenib received Breakthrough Therapy Designation (BTD) by the FDA for the treatment of R/R NPM1-mutant AML based on data from Kura’s ongoing KOMET-001 clinical trial. Additional information about clinical trials for ziftomenib can be found at kuraoncology.com/clinical-trials/#ziftomenib.