Enasidenib Plus Venetoclax Demonstrates Promising Activity for Relapsed/Refractory IDH2-Mutant AML: ENAVEN-AML Trial
The combination of enasidenib and venetoclax showed encouraging clinical activity and a manageable safety profile among patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) who have an IDH2 mutation, according to results from the ENAVEN-AML trial published in The Lancet Haematology.
Previous research has shown efficacy for enasidenib, an IDH2 inhibitor, in addition to treatment with venetoclax, a BCL2 inhibitor, among patients with IDH2-mutated AML. Researchers conducted a phase 1b/2 trial to evaluate the safety and efficacy of enasidenib plus venetoclax across 2 centers in Canada.
Overall, 27 patients were treated between November 2020 and July 2022. Patients included had R/R AML or myelodysplastic syndrome (MDS) with a confirmed IDH2 mutation and had received at least 1 prior line of therapy. The median age of all patients was 70 years (interquartile range [IQR], 55 to 76) and 59% of patients were male. Only 1 patient had MDS, while 96% had R/R AML. Treated patients received venetoclax 400 mg orally daily, including a 3-day ramp-up, starting on cycle 1 day 1, followed by enasidenib 100 mg daily beginning on cycle 1 day 15.
At a median follow-up of 20.2 months (IQR, 15.0 to 23.0), the overall response rate (ORR) was 62% (95% confidence interval [CI], 41 to 80) and the complete remission (CR) rate was 50% among the 26 AML patients. The 1 MDS patient did not respond to treatment with enasidenib plus venetoclax.
In terms of safety, the most common grade ≥3 treatment-emergent adverse events were febrile neutropenia (41%), infections (30%), thrombocytopenia (26%), pneumonia (22%), sepsis (19%), and anemia (19%). Serious adverse events occurred in 62% of patients, of which the most common were infection (41%) and intracranial hemorrhage (19%).
The researchers concluded, “enasidenib plus venetoclax is safe, with no unexpected [treatment-emergent adverse events] (TEAEs) or treatment-related deaths, and shows preliminary activity in patients with relapsed or refractory IDH2-mutated AML and MDS.”
Source:
Richard-Carpentier G, Gupta G, Koraksic C, et al. Enasidenib plus venetoclax in patients with IDH2-mutated relapsed or refractory acute myeloid leukaemia or myelodysplastic syndrome (ENAVEN-AML): a multicentre, single-arm, phase 1b/2 trial. The Lancet Haematology. Published online October 8, 2025. doi:10.1016/s2352-3026(25)00254-6
