FDA Grants Breakthrough Therapy Status to Ziftomenib in R/R NPM1+ AML

Supporting findings for the breakthrough therapy designation came from the phase 1/2 KOMET-001 trial (NCT04067336).

The FDA has granted breakthrough therapy designation to ziftomenib as a treatment for those with relapsed/refractory acute myeloid leukemia (AML) harboring NPM1 mutations, according to a press release from the developers Kura Oncology, Inc.¹

Supporting findings for the breakthrough therapy designation came from the phase 1/2 KOMET-001 trial (NCT04067336).

According to findings presented at the 2023 Annual Meeting of the Society of Hematologic Oncology, ziftomenib at 600 mg elicited a complete remission (CR) rate of 35% among 20 evaluable patients.² Additionally, the composite CR rate was 40%, the overall response rate (ORR) was 45%, and the median time to first response was 51 days. Investigators also reported a median duration of response (DOR) of 8.2 months (95% CI, 1.0-not evaluable [NE]) after a median follow-up of 8.8 months.

Any-grade treatment-emergent adverse effects (TEAEs) affected 95% of patients, with the most common toxicities comprising diarrhea (45%), hypokalemia (40%), and nausea (30%). Investigators highlighted no instances of treatment-related QTc prolongation. Additionally, 1 report of grade 3 differentiation proved to be manageable with a mitigation strategy.

Developers anticipate completing the registration-directed KOMET-001 trial by mid-2024. Additionally, investigators are assessing ziftomenib in combination with venetoclax (Venclexta)/azacitidine or cytarabine/daunorubicin for patients with NPM1-mutated AML harboring KMT2A rearrangements as part of the phase 1 KOMET-007 trial (NCT05735184). Treatment with ziftomenib plus gilteritinib (Xospata) or other standard therapy options for NPM1-mutant, KMT2A-rearranged AML is also being evaluated in the phase 1 KOMET-008 trial (NCT06001788).

“We are highly encouraged by FDA’s decision to grant breakthrough therapy designation to ziftomenib, recognizing its potential as an innovative medicine for patients with relapsed/refractory NPM1-mutant AML,” Troy Wilson, PhD, JD, president and chief executive officer at Kura Oncology, said in the press release.¹

“NPM1-mutant AML represents approximately 30% of new AML cases annually, and this designation reflects that NPM1-mutant AML is a disease of significant unmet need for which there is no approved targeted therapy as well as the fact that ziftomenib offers potential to demonstrate substantial improvement over available therapies. We remain committed to bringing ziftomenib to the market as quickly as possible and look forward to working more closely with FDA to bring our ziftomenib program to patients in urgent need of effective treatments,” he added.

In the ongoing, first-in-human, phase 1/2 KOMET-001 trial, patients will receive ziftomenib at the recommended phase 2 dose of 600 mg once daily.

The primary end point of the trial’s phase 2 registration-enabling portion is the CR or CR with partial hematological recovery rate (CRh). The trial’s secondary end points include the duration of CR/CRh, transfusion independence, CR/CRh measurable residual disease (MRD) negativity, and AEs.

Patients 18 years and older with relapsed/refractory AML who have progressed on or are ineligible to receive standard therapies such as hematopoietic stem cell transplantation are eligible for enrollment on the trial.³ Additional eligibility criteria include having an ECOG performance status of 0 to 2, a minimum life expectancy of 2 months, and adequate liver and kidney function.

Those who have a diagnosis of acute promyelocytic leukemia or chronic myelogenous leukemia in blast crisis are ineligible for enrollment on the trial. Having clinically active central nervous system leukemia; a donor lymphocyte infusion in less than 30 days before study entry; an active acute or chronic systemic fungal, bacterial, or viral infection; significant cardiovascular disease; and major surgery within 4 weeks of beginning study treatment are also grounds for exclusion from the trial.

References

1. Kura Oncology receives breakthrough therapy designation for ziftomenib in NPM1-mutant AML. News release. Kura Oncology, Inc. April 22, 2024. Accessed April 23, 2024. https://tinyurl.com/muzr3bye
2. Erba HP, Wang ES, Issa GC, et al. Activity, tolerability and resistance profile of the menin inhibitor ziftomenib in adults with relapsed or refractory NPM1-mutated AML. Presented at: Society of Hematologic Oncology Annual Meeting 2023; September 6-9, 2023; Houston, TX. AML-475.
3. First in human study of ziftomenib in relapsed or refractory acute myeloid leukemia. ClinicalTrials.gov. Accessed April 23, 2024. https://tinyurl.com/5ct2yz8y