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.

Abstract

BACKGROUND Enasidenib, a mutant IDH2 inhibitor, is used to treat IDH2-mutated acute myeloid leukaemia (AML). Preclinical studies have demonstrated synergy between enasidenib and venetoclax, a BCL2 inhibitor, in IDH2-mutated AML. The aim of this study was to evaluate the safety and activity of enasidenib plus venetoclax in patients with relapsed or refractory IDH2-mutated AML or myelodysplastic syndromes (MDS). METHODS The ENAVEN-AML study was a single-arm, phase 1b/2 trial conducted at two centres in Canada. Patients were eligible to participate if they were 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 to 2, had a confirmed IDH2 mutation (affecting Arg140 or Arg172), and had AML or MDS that was refractory or had relapsed after at least one line of treatment. Patients were treated with venetoclax 400 mg orally daily with a 3-day dose ramp-up starting on cycle 1 day 1 and enasidenib 100 mg orally daily starting on cycle 1 day 15. The primary endpoint of the phase 1b portion was safety, which included dose-limiting toxicity and the frequency and severity of treatment-emergent adverse events (TEAEs), as well as determining the maximum tolerated dose and recommended phase 2 dose. The primary objective of the phase 2 portion was to assess preliminary activity, with overall response rate by intention-to-treat as the primary endpoint. Assessment of safety and activity were determined on the pooled analysis data from the phase 1 and 2 studies. The ENAVEN-AML study is registered with ClinicalTrials.gov (NCT04092179) and is completed. FINDINGS From Nov 12, 2020, to July 5, 2022, the study enrolled 27 patients (13 in phase 1b, 14 in phase 2) and the median follow-up was 20·2 months (IQR 15·0-23·0) at the data cutoff on Sept 30, 2023. The median age was 70 years (IQR 55-76); 16 (59%) of 27 patients were male, 11 (41%) female, and 19 (70%) White. 26 patients had relapsed or refractory AML, and one patient had relapsed MDS. The most common grade 3 or worse TEAEs were febrile neutropenia (n=11, 41%), infections (n=8, 30%), thrombocytopenia (n=7, 26%), pneumonia (n=6, 22%), sepsis (n=5, 19%), and anaemia (n=5, 19%). One case of IDH inhibitor-associated differentiation syndrome was observed. Serious adverse events were reported in 17 (62%) of 27 patients, most commonly infections (n=11, 41%) and intracranial bleeding (n=5, 19%). No dose-limiting toxicities or treatment-related deaths were observed. The recommended phase 2 dose was 400 mg daily for venetoclax and 100 mg daily for enasidenib. Of the 26 patients with AML, the overall response rate was 62% (95% CI 41-80; 16 of 26), with 13 (50%) of 26 having complete remission. The only patient with MDS did not respond to enasidenib plus venetoclax. INTERPRETATION Enasidenib plus venetoclax is safe, with no unexpected TEAEs or treatment-related deaths, and shows preliminary activity in patients with relapsed or refractory IDH2-mutated AML and MDS. FUNDING AbbVie and Bristol Myers Squibb.