Ziftomenib Combos Show Early Safety, Activity in NPM1-Mutant and KMT2A-Rearranged AML

Amer Zeidan, MBBS, MHS

Ziftomenib paired with standard-of-care approaches like cytarabine and daunorubicin (7+3) and venetoclax (Venclexta) plus azacitidine (Vidaza) was found to have acceptable tolerability with preliminary evidence of clinical activity in patients with NPM1-mutant and KMT2A-rearranged acute myeloid leukemia (AML), according to early data from the phase 1/2 KOMET-007 trial (NCT04067336).¹

In 5 patients with newly diagnosed disease and 15 patients with relapsed or refractory disease, continuous ziftomenib given at a daily dose of 200 mg was well tolerated with a toxicity profile that proved to align with features of underlying disease and backbone therapies. No dose-limiting toxicities occurred, nor were there any differentiation syndrome events or drug-drug-interactions. No additive myelosuppression or evidence of QTc prolongation were observed.

In those with newly diagnosed disease and adverse risk who received ziftomenib plus 7+3, all patients achieved a complete remission (CR) with full count recovery. Of the 5 responders, 4 had tumors harboring NMP1 mutations and 1 had a tumor harboring a KMT2A rearrangement.

Fifty-three percent of patients with relapsed or refractory disease who received ziftomenib plus venetoclax and azacitidine responded to treatment. In the menin inhibitor­–naive patients (n = 9), the overall response rate (ORR) was 78%, the CR/CRi rate was 67%, and the CR/CRh rate was 56%. Within this group, 5 patients had NPM1-mutated disease and 4 had KMT2A rearrangements. In the former group, the ORR was 100%, and in the latter group, the ORR was 50%. In the venetoclax-exposed subset (n = 10), the ORR was 40%, the CR/CRi rate was 30%, and the CR/CRh rate was 30%. Five of these patients had NPM1-mutated disease and the other 5 had KMT2A-rearranged disease; the respective ORRs in these groups were 60% and 20%, respectively.

“In this first public release of early data from the KOMET-007 trial, ziftomenib demonstrates an encouraging safety and tolerability profile in combination with 7+3 and venetoclax/azacitidine, enabling continuous administration while mitigating the risk of differentiation syndrome,” Amer Zeidan, MBBS, MHS, interim 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, 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.”

Cohorts of patients with NPM1 mutations and KMT2A rearrangements were enrolled independently.² For those with newly diagnosed disease, ziftomenib dosing started at 200 mg (dose level [DL] 1). This DL is currently enrolling and aims to treat at least 6 patients.

Dosing with ziftomenib will begin in day 8 of cycle 1 and given continuously thereafter. Cytarabine will be given on days 1 through 7 of cycle 1 and daunorubicin will be given on days 1 to 3 of cycle 1 with the potential for an additional cycle of each agent based on cycle 1 bone marrow biopsy results.

Dose-escalation will be conducted in those with adverse risk, defined as those older than 60 years and/or with treatment-related AML and/or adverse-risk cytogenetics. Doses will escalate to 400 mg (DL2) and 600 mg (DL3). Investigators are also evaluating ziftomenib at 100 mg in these patients (DL-1). After the recommended phase 2 dose (RP2D) is selected for ziftomenib plus 7+3, investigators plan to expand to treat up to 20 first-line intensive-chemotherapy patients to validate the dose.

In those with relapsed or refractory disease, ziftomenib was first evaluated at DL1. Patients are currently being enrolled to DL2. Ziftomenib dosing began on day 8 of cycle 1 and would be continuously administered thereafter. Venetoclax will be given according to the label as part of 28-day cycles with adjustments to cycle length based on cycle 1 bone marrow biopsy results. Azacitidine will be given according to the label on days 1 to 7 of each cycle with additional cycles based on the bone marrow biopsy results.

The agent is also being explored in DL -1 and will be explored at DL3. Once the RP2D for ziftomenib plus venetoclax/azacitidine is determined, investigators plan to expand to 3 groups: treating up to 20 first-line non-intensive chemotherapy patients, up to 20 relapsed or refractory patients, and to examine ziftomenib plus venetoclax only in up to 20 patients with relapsed or refractory disease—all to validate the RP2D.

As of the data cutoff date of January 11, 2024, 80% of the 20 patients are still on trial, which includes all of the patients with NPM1-mutated disease. In the total population, the median patient age was 55.5 years (range, 23-77) and 65% of patients were female. Regarding genetic subtypes, 55% had NPM1 mutations and 45% had KMT2A rearrangements. Slightly more than half of patients (55%) had an ECOG performance status of 1, 25% had a status of 2, and 20% had a status of 0. Prior antineoplastic therapies received included stem cell transplant (47%), hypomethylating agent (53%), venetoclax (67%), and menin inhibitors (40%).

Additional safety findings showed that grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 90% of patients. The most common grade 3 or higher TEAEs to occur in at least 10% of patients included decreased platelet count (30%), febrile neutropenia (25%), decreased white blood cell count (20%), pneumonia (15%), hypoxia (10%), decreased neutrophil count (10%), sepsis (10%), and thrombocytopenia (10%).

Grade 3 or higher ziftomenib-related adverse effects (AEs) occurred in 30% of patients. The most common grade 3 or higher treatment-related AEs included decreased platelet counts (15%), anemia (5%), febrile neutropenia (5%), leukopenia (5%), neutrophil count (5%), and thrombocytopenia (5%).

References

1. Kura Oncology reports positive preliminary ziftomenib combination data in acute myeloid leukemia. News release. Kura Oncology, Inc. January 30, 2024. Accessed January 31, 2024. https://ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-reports-positive-preliminary-ziftomenib
2. Kura Oncology Virtual Investor Event. Kura Oncology, Inc. January 30, 2024. Accessed January 31, 2024. https://ir.kuraoncology.com/events-presentations/events