NEW YORK – Syndax Pharmaceuticals said it will submit a new drug application to the US Food and Drug Administration seeking approval for its menin inhibitor revumenib as a treatment for KMT2A-rearranged acute leukemia by year-end following a positive data readout from the pivotal Phase II AUGMENT-101 trial.
City of Hope hematologist Ibrahim Aldoss said in a presentation of the results at the American Society of Hematology's annual meeting on Tuesday that the study in KMT2A-rearranged acute leukemia patients was stopped early after the AUGMENT-101 trial met its primary efficacy endpoint during a predefined interim analysis, and based on this data, Syndax is initiating a new drug application for revumenib in this setting under the FDA's Real-Time Oncology Review program.
Revumenib is a small molecule designed to inhibit the menin-KMT2A interaction. Syndax is testing the drug's activity in the AUGMENT-101 trial in patients with relapsed or refractory acute myeloid, acute lymphoblastic, or other acute leukemias harboring a KMT2A rearrangement or NPM1 mutation. (A cohort of patients with NPM1-mutated acute myeloid leukemia is not included in the analysis presented at ASH, and the study continues to enroll these patients at all sites.)
KMT2A rearrangements occur in up to 10 percent of acute myeloid and acute lymphoblastic leukemias and are associated with poor outcomes including a five-year overall survival rate of less than 25 percent. Patients frequently relapse after chemotherapy or hematopoietic stem cell transplant. In adults, the remission rate after relapse is 5 percent and median overall survival is 2.4 months. KMT2A rearrangements are also found in 80 percent of infant ALL and 5 to 15 percent of children and adults with acute leukemias. Outcomes in infants and children following relapse are also poor, and there are no targeted therapies approved for KMT2A-rearranged disease.
In March, Syndax published results in Nature from 68 patients enrolled in the Phase I dose-escalation portion of the AUGMENT-101 trial showing a 30 percent complete remission rate with revumenib. The overall response rate was 53 percent, including patients who had a complete remission, those who had complete remission with incomplete platelet recovery or with incomplete hematologic recovery, and patients in a morphologic leukemia-free state. The median time to complete remission was 1.9 months, and the median duration of response was 9.1 months. Median overall survival was seven months.
The latest Phase II results presented at the meeting involved 57 adult and pediatric patients with KMT2A-rearranged acute leukemia who had received a median of two (and up to 11) prior lines of therapy. Nearly half of the patients had three or more prior treatments, the majority had received Genentech's BCL2 inhibitor Venclexta (venetoclax), and nearly half had failed a prior allogeneic stem cell transplant.
The interim analysis was triggered when 57 patients with centrally confirmed KMT2A alterations had completed six months of follow-up or discontinued therapy. At interim analysis, 23 percent of patients were in complete remission or complete remission with partial hematologic recovery, which was the primary endpoint in the trial. The overall response rate on revumenib was 63 percent at a median follow-up of 6.1 months. The median duration of response was 6.4 months.
Out of 10 patients who had a complete remission or complete remission with partial hematologic recovery and also had known measurable residual disease status, seven achieved MRD negativity. Median overall survival was eight months.
The investigators saw responses to revumenib across subgroups, including patients who'd had and who didn't have prior transplants and patients with varying prior lines of treatment, as well as in children and adults. Aldoss noted that the size of each subgroup was small, and the study was not powered to measure differences between them.
Aldoss pointed out, though, that patients who had received Venclexta previously had a lower response rate, in the range of 15 percent, compared to the 44 percent response rate in patients who had never had Venclexta.
The safety profile was manageable overall with 6.4 percent of patients discontinuing therapy for treatment-related adverse events.
At the meeting, Syndax also reported data from patients with KMT2A-rearranged AML who received revumenib within the Phase I BEAT AML and the AUGMENT-102 trials. The composite complete remission rate was 100 percent among the 13 evaluable newly diagnosed patients with NPM1-mutated or KMT2A-rearranged AML in the dose-escalation phase of BEAT AML. Eleven patients, or 85 percent, achieved a complete remission or complete remission with partial hematologic recovery. Twelve of those patients, or 92 percent, achieved MRD-negative status.
In the AUGMENT-102 trial, Syndax is testing revumenib combined with fludarabine-cytarabine chemotherapy in pediatric patients with relapsed or refractory AML harboring NPM1 mutations, NUP98 rearrangements, and KMT2A rearrangements. Out of 12 patients, four achieved a composite complete remission on the regimen, including three who had a complete response.