Cancer Research: From Basic to Bedside, A Comprehensive Overview
BACKGROUND: The isocitrate dehydrogenase 2 (IDH2) gene is mutated in ∼10–15% cases of acute myeloid leukemia (AML) and ∼5% cases of myelodysplastic syndromes (MDS). Enasidenib (ENA) is an oral selective IDH2 inhibitor used for treatment of IDH2-mutated (mIDH2) relapsed/refractory (R/R) AML. Preclinical studies showed that mIDH2 AML cells are particularly sensitive to BCL2 inhibition with venetoclax (VEN) and combination of ENA and VEN is more effective than single agents in patient-derived xenograft models of mIDH2 AML. Based on this rationale, we conducted a phase Ib/II trial evaluating the safety and efficacy of ENA plus VEN in patients (pts) with mIDH2 R/R AML or MDS (NCT04092179).
METHODS: This single-arm phase Ib/II trial was conducted at the Princess Margaret Cancer Centre and the University of Alberta Hospital in Canada. Pts ≥ 18 years with mIDH2 R/R AML or MDS, adequate organ function and ECOG performance status ≤ 2 were eligible. Participants were not eligible if they had prior exposure to IDH2 or BCL2 inhibitors. Pts were treated continuously by 28-day cycles of VEN 400 mg daily starting with a 3-day ramp-up on cycle 1 day 1 and with ENA 100 mg daily starting on cycle 1 day 15. The primary endpoints were safety, tolerability and recommended phase 2 dose (RP2D) for the phase Ib part and overall response rate (ORR) for the phase II part. ORR included complete remission (CR), CR with partial hematological recovery (CRh), CR with incomplete hematological recovery (CRi), morphologic leukemia-free state (MLFS) and partial remission (PR) as defined by the European Leukemia Network (ELN). Duration of response (DOR), overall survival (OS), pharmacokinetic (PK) analysis for VEN and bone marrow (BM) IDH2 variant allele frequency (VAF) by droplet digital PCR (ddPCR) were also evaluated.
RESULTS: From November 2020 to July 2022, 27 pts were enrolled: 12 in the phase Ib and 15 in the phase II. Almost all pts had AML, except one with MDS who progressed on treatment with azacitidine. The data cutoff date was June 30, 2023. The median age was 70 years (range, 23–84) (Table 1). Patients had a median of 1 prior line of treatment (range, 1–2) including 5 (19%) who had previously undergone allogeneic stem cell transplant (HSCT). Fifteen (56%) and 12 (44%) pts had R140Q and R172K/W IDH2 mutation (mut), respectively. The median BM IDH2 VAF at baseline was 23.4 (range 2.3–49.9).