Ziftomenib/Standard Therapy Yields 100% CR Rate in NPM1+ or KMT2A+ AML Subset

“Ziftomenib is one of the most exciting investigational agents being studied in AML, and I am thrilled to see the rapid pace of accrual into this first-in-human combinational study,” according to Amer Zeidan, MBBS, MHS.

Treatment with ziftomenib in combination with standard-of-care options demonstrated encouraging preliminary clinical activity and tolerability in a small population of patients with NPM1-mutated or KMT2A-rearranged acute myeloid leukemia (AML), according to a press release on early findings from the phase 1 KOMET-007 trial (NCT05735184).

As of the data cutoff date of January 11, 2024, a complete remission (CR) with full count recovery was observed in 100% (n = 5/5) of those who received ziftomenib plus cytarabine/daunorubicin (7+3). Of those with an observed response, 4 had NPM1-mutated disease, and 1 had KMT2A rearrangements.

Investigators reported an overall response rate (ORR) of 53% (n = 8/15) among those with relapsed/refractory disease who received ziftomenib plus venetoclax (Venclexta) and azacitidine; 40% (n = 6/15) were previously treated with a menin inhibitor. The rate of CR or CR with partial hematologic recovery (CRh) was 56% (n = 5/9) in patients who received no prior treatment with a menin inhibitor, which included 60% (n = 3/5) of those with NPM1 mutations and 50% (n = 2/4) of those with KMT2A rearrangements. Additionally, the ORR was 40% (n = 4/10) in those previously treated with venetoclax, including 60% (n = 3/5) of those with NPM1 mutations.

Treatment with ziftomenib appeared to be well tolerated at 200 mg once a day. Investigators highlighted no any-grade differentiation syndrome events, dose-limiting toxicities, drug-drug interactions, or additive myelosuppression. Overall, 80% (n = 16/20) of patients remained on study treatment as of the data cutoff, which included all 11 patients with NPM1 mutations.

Enrollment for the trial’s 400-mg dosing cohort is ongoing, and the 200-mg dose received clearance in the relapsed/refractory venetoclax/azacitidine cohorts. After determining a recommended phase 2 dose, developers look to launch a phase 1b dose validation or expansion trial combining ziftomenib with venetoclax/azacitidine in patients with newly diagnosed NPM1-mutant or KMT2A-rearranged AML.

“Ziftomenib is one of the most exciting investigational agents being studied in AML, and I am thrilled to see the rapid pace of accrual into this first-in-human combinational study,” lead study investigator Amer Zeidan, MBBS, MHS, chief of the Division of Hematologic Malignancies and director of Hematology Early Therapeutics Research at Yale Cancer Center, stated in the press release. “The combinations demonstrate encouraging preliminary evidence of clinical activity in patients with refractory/relapsed disease after failure of other agents, including venetoclax, a setting with very limited effective treatment options. Further, the fact that most patients remain on study as of the data cutoff is notable in such difficult-to-treat patient populations.”

The trial’s primary end points include dose-limiting toxicities, adverse effects, and CR rate. Secondary end points include the composite CR rate, measurable residual disease, overall survival, event-free survival, and duration of response.

Patients 18 years and older with confirmed newly diagnosed or relapsed/refractory AML harboring NPM1 mutations or KMT2A rearrangements and an ECOG performance status of 0 to 2 can enroll on the trial. Additional eligibility criteria include having adequate liver, renal, and cardiac function.

“We are highly encouraged by these preliminary combination data for ziftomenib and believe they support advancement into the frontline AML population. Given that ziftomenib targets foundational mutations at the core of up to 50% of AML cases, we are encouraged by its potential to transform treatment outcomes across the continuum of care,” Troy Wilson, PhD, JD, president and chief executive officer at Kura Oncology, the developer of ziftomenib, concluded in the press release.

Reference

Kura Oncology reports positive preliminary ziftomenib combination data in acute myeloid leukemia. News release. Kura Oncology, Inc. January 30, 2024. Accessed January 30, 2024. http://tinyurl.com/yetb6x8z