In the Augment-101 phase 2 study, 63% of patients experienced overall response rate with revumenib.
Ibrahim Aldoss, MD, a hematologist and oncologist with City of Hope Comprehensive Cancer Center, Duarte, California, sat down with Pharmacy Times at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, taking place December 9-12, 2023, in San Diego, California. Aldoss discusses positive topline data from a pivotal phase 2 study evaluating revumenib (Syndax) for relapsed/refractory (r/r) KMT2A-rearranged acute leukemia. He also breaks down the therapeutic need for this drug, its mechanism of action, and positive safety and efficacy data.
PT Staff: What characterizes this type of leukemia, and what are the most pressing barriers to care right now?
Ibrahim Aldoss, MD: So KMT2A rearranged (KMT2Ar) disease accounts for 10% of all acute leukemias and can present as lymphoid or myeloid leukemia; it can affect children, infants and adults as well [and] it's a disease with unmet therapeutic need. There is high risk of relapse after standard chemotherapy and stem cell transplant, and currently there is no available target therapy for KMT2Ar disease. For relapse patients, the response rate is low, as well as the median overall survival (OS). So it's an area of unmet therapeutic need.
PT Staff: What is the mechanism of action of revumenib, which is being assessed for the treatment of this disease?
Ibrahim Aldoss, MD: So, revumenib is a small molecule inhibitor of the KMT2Ar-menin interaction, which is responsible for driving the leukemogenesis and KMT2Ar leukemias as well as other leukemias associated with Hox upregulation, including nucleophosmin-1 (NPM1)-mutated AML. In preclinical studies, revumenib can induce differentiation of leukemia cells and decrease the expression of Hox A. And because its interaction with cytochrome P450 3A4 (CYP3A4) inhibitors in a phase 1 study, we identify the recommended phase 2 dosing for humans, in combination with a not strong CYP3A4 inhibitor, with a strong CYP3A4 inhibitor, as well as moderate CYP3A4 inhibitor.
PT Staff: What were findings from the pivotal Augment-101 Phase 2 study, and how can they impact the treatment landscape of this disease?
Ibrahim Aldoss, MD: The Augment-101 phase 2 study includes all patients, or children and adults, with relapsed/refractory KMT2Ar acute leukemia (including AML/ALL acute leukemia with ambiguous lineage). There was a prespecified interim analysis after the first 57 patients with centrally confirmed mutation and had adequate follow-up in the study.
The findings were that, for these heavily pretreated patients (with a quarter of the patient being refractory to initial therapy and never achieving remission [and] the majority having prior venetoclax [and half or close to half of patients having prior transplant]) we saw a very encouraging response rate— the overall response rate (ORR) was 63%. And the primary endpoint was complete remission (CR) plus CR with partial hematologic recovery (CRh) rate, and the study made the primary efficacy with CR plus CR rate of 23%.
The majority of responders who had minimal residual disease (MRD) assessment locally had achieved MRD negativity, and the median duration of response (DoR) for those who achieved CR and CRh was 6.4 months. And almost 40% of responders were able to proceed with allogeneic stem cell transplant as a curative consolidation therapy for them; after the transplant, half of the patients were able to continue revumenib as a maintenance therapy.
The implication of the results, I mean, it shows that reasonably safe and effective monotherapy for patients with r/r KMT2Ar leukemias, it is used for durable and deep remissions and has allowed many of those patients to transition to curative allogeneic stem cell transplant. And as the study met the primary efficacy endpoint at the interim analysis, this led to a study to be stopped. The company is filing an FDA application for the drug approval for this entity of patients. Now with these encouraging results and a safety profile, revumenib has been combined with other agents in the r/r setting and it is being moved early in the treatment paradigm of acute leukemia with KMT2Ar.