Item 8.01 Other Events.
On December 10, 2022, Kura Oncology, Inc. (the “Company”) announced updated clinical data from KOMET-001, a Phase 1/2 trial of the Company’s potent and selective menin inhibitor, ziftomenib, that were presented at an oral presentation at the 2022 Annual Meeting of the American Society of Hematology.
In the Phase 1a dose-escalation trial, ziftomenib demonstrated a wide therapeutic window and encouraging monotherapy activity in an all-comer population of 30 patients with relapsed/refractory acute myeloid leukemia (“AML”), including a complete remission (“CR”) with no evidence of minimal residual disease (“MRD”) in a nucleophosmin 1 (“NPM1”)-mutant patient with DNMT3A and Lysine K-specific Methyl Transferase 2A (“KMT2D”) co-mutations. The patient entered the trial having progressed through seven prior lines of therapy and remains on ziftomenib after two years.
In order to inform an optimal Phase 2 dose and in consultation with the U.S. Food and Drug Administration (“FDA”) and its Project Optimus initiative, the Company conducted a Phase 1b trial with two randomized expansion cohorts, each comprised of NPM1-mutant and KMT2A-rearranged AML patients. A total of 53 patients were ultimately treated in the Phase 1b trial: 17 at 200 mg and 36 at 600 mg. These patients were heavily pretreated and received a median of three prior lines of therapy (range 1-11), with the majority of patients having received prior venetoclax and a quarter having progressed after at least one prior stem cell transplant. As of the data cutoff on October 24, 2022, 10 of the patients treated at 600 mg remained on ziftomenib and 17 were still in follow-up. Median duration of response has not been reached.
Ziftomenib demonstrated optimal clinical benefit at 600 mg with a 30% CR rate (6/20) in patients with NPM1-mutant AML, compared to 17% (1/6) at 200 mg. Notably, four of the six NPM1-mutant patients who achieved a CR at 600 mg had IDH and/or FLT3 co-mutations. Overall, four of the seven patients with IDH co-mutations achieved a CR on ziftomenib. Of the five patients assessed for MRD at 600 mg, three were MRD negative.
Although meaningful clinical benefit was observed in patients with KMT2A rearrangements, symptoms of differentiation syndrome prevented most patients from receiving sufficient therapy to attain response criteria for CR or CR with partial hematologic recovery (“CRh”), and only one patient achieved a CR/CRh.
Continuous daily dosing of ziftomenib has been well tolerated. Reported adverse events most often were consistent with features of underlying disease. No evidence of drug-induced QTc prolongation was observed. Six patients discontinued due to adverse events; however, none of these were considered treatment related. The most common treatment-emergent adverse event observed was differentiation syndrome (“DS”), a known adverse event related to AML treatments that promote differentiation of AML cells. Of the 20 NPM1-mutant patients treated at 600 mg, four (20%) experienced DS; three of these events were less than Grade 3, and only one of these events (5%) was Grade 3. For KMT2A-rearranged patients, rates of DS were similar across doses, and approximately 38% of patients experienced DS; 25-30% of treated KMT2A-rearranged patients experienced Grade 3 or greater events.
The Company believes the higher incidence of DS observed in the KMT2A-rearranged patients is due to their much higher incidence of disease in extramedullary (outside of the bone marrow) sites, induced to differentiate by the high tissue penetrance demonstrated by ziftomenib preclinically. By combining ziftomenib with appropriate standards of care, the Company believes it can reduce this extramedullary disease burden and consequent DS symptoms, keep patients on ziftomenib therapy longer and drive superior treatment outcomes in patients with KMT2A-rearranged AML.
The Company also announced that 600 mg has been determined as the recommended Phase 2 dose for ziftomenib in NPM1-mutant AML following a positive Type C meeting with the FDA. Agreement was also reached on key elements of a registration-enabling study design, and the Company is now preparing to initiate the Phase 2 registration-directed trial. The Company expects to dose the first patient in the first quarter of 2023, followed by a series of combination studies in frontline and relapsed/refractory AML that will prioritize development with venetoclax and FLT3 in combination.
